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Epidemiology of natural transmission of bovine leukemia virus infection

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Epidemiology of natural transmission of bovine leukemia virus infection
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Bovine leukemia virus infection
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Thurmond, Mark Cy, 1947-
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ix, 167 leaves : ill. ; 28 cm.

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Antibodies ( jstor )
Bovine leukemia virus ( jstor )
Calves ( jstor )
Cattle ( jstor )
Dams ( jstor )
Deltaretrovirus infections ( jstor )
Herds ( jstor )
Infections ( jstor )
Leukemia ( jstor )
Trucks ( jstor )
Bovine leukosis ( lcsh )
Cattle -- Diseases ( lcsh )
Leukemia in animals ( lcsh )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 1982.
Bibliography:
Includes bibliographical references (leaves 145-165).
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Typescript.
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Vita.
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by Mark Cy Thurmond.

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EPIDEMIOLOGY OF NATURAL TRANSMISSION
OF BOVINE LEUKEMIA VIRUS INFECTION










BY


MARK CY THURMOND


A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL
FULFILLMENT OF THE REQUIREMENTS FOR
THE DEGREE OF DOCTOR OF PHILOSOPHY



UNIVERSITY OF FLORIDA
1982


1
























Copyright 1982



by



Mark Cy Thurmond























DEDICATED TO

AUDREY














ACKNOWLEDGEMENTS


Technical assistance with agar-gel immunodiffusion and

animal sampling was provided by Ms. J. Hennemann, Ms. J.

Ring, Mr. C. Maden, Mr. T. O'Donnell, Mr. A. Green, and

Mr. J. Lindsey. Most data management and computer program-

ming were performed by Ms. J. Galvez and Mr. D. Puhr. Edi-

torial assistance was provided by Dr. M. Burridge, Dr. P.

Nicoletti, and Dr. C. Wilcox. The typist was Ms. B.

Smerage. The valuable support and discussions offered by

the following people are gratefully acknowledged: Dr. M.

Burridge, Dr. R. Carter, Dr. M. Drost, Dr. C. Franti

(University of California/Davis), Dr. J. Gaskin, Dr. R.

Kahrs, Dr. J. Miller (USDA, Ames, IA), Dr. K. Portier,

Dr. O. Straub (West Germany), Dr. M. Van Der Maaten (USDA,

Ames, IA), Dr. S. Walter (Yale University), and Dr. C.

Wilcox. Additional thanks is extended to Dr. R. Carter,

Dr. K. Portier, and Dr. C. Wilcox for their interest and

support in statistical designs and analyses. Financial aid

was provided by United States Department of Agriculture

cooperative agreement 58-519B-0-872 and by the Wetterburg

Foundation of Newark, New Jersey.















TABLE OF CONTENTS


PAGE


ACKNOWLEDGEMENTS .

ABSTRACT .


CHAPTER


I INTRODUCTION .

II LITERATURE REVIEW .


4
. 4


Bovine Leukemia Virus Infection .
Bovine Leukemia Virus. .
Pathogenesis .
Transmission Via Excretions and
Secretions .
Serology .
Factors Examined for Associations with
Bovine Leukemia Virus Infection .
Transmission of Bovine Leukemia Virus
Infection .
Infection in Other Domestic Animals. .
Reviews .

GENERAL MATERIALS AND METHODS .

Population Studied .
Location and Climate .
Management Practices .
Sampling Design .
Demographic Information .
Serology .
Other Species Examined .
Diseases or Conditions Observed. .
Data Collection and Computer Programs.

IN UTERO TRANSMISSION OF BOVINE LEUKEMIA
VIRUS .

Introduction .
Materials and Methods .
Results .
Discussion .


III


S 4
S 5
S 6

S 8
S 9

S 9

S. 13
S. 16
S. 17


. viii









PAGE

V DECAY OF COLOSTRAL ANTIBODIES TO BOVINE
LEUKEMIA VIRUS 41

Introduction .. 41
Materials and Methods. .. 41
Results .. 44
Discussion .. 45

VI AGE-SPECIFIC RATES OF DETECTION OF BOVINE
LEUKEMIA VIRUS INFECTION 53

Introduction 53
Materials and Methods ... 54
Results. .. 58
Discussion . 60

VII SEASONAL PATTERNS OF RATES OF BOVINE
LEUKEMIA VIRUS INFECTION .. 83

Introduction 83
Materials and Methods. .. 84
Results. .. 86
Discussion ... 87

VIII SPATIAL PATTERNS OF BOVINE LEUKEMIA VIRUS
INFECTION. . 98

Introduction ... 98
Materials and Methods. .. 99
Results. . 104
Discussion . 105

IX IATROGENIC TRANSMISSION OF BOVINE LEUKEMIA
VIRUS INFECTION. 118

Introduction .. 118
Materials and Methods. .. .118
Results. .. .120
Discussion .. 120

X SUMMARY . 129

APPENDICES

A PLAT OF THE UNIVERSITY OF FLORIDA DAIRY
RESEARCH UNIT. 134

B AVERAGE MONTHLY HIGH AND LOW TEMPERATURES
AND RAINFALL BETWEEN JULY 1, 1979, AND
SEPTEMBER 30, 1981, FOR GAINESVILLE,
FLORIDA. . 135









PAGE


C MONTHLY FREQUENCIES OF CALVES BORN ALIVE
BETWEEN JULY 1, 1979, AND JUNE 30, 1981,
AT THE UNIVERSITY OF FLORIDA DAIRY
RESEARCH UNIT. .. .136

D LOCATION SITES AT THE DAIRY RESEARCH UNIT 137

E PRECIPITATION LINES OF AGAR-GEL IMMUNO-
DIFFUSION. .. .144

LIST OF REFERENCES. .. .145

BIOGRAPHICAL SKETCH ... .166


vii














Abstract of Dissertation Presented to the Graduate Council
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy


EPIDEMIOLOGY OF NATURAL TRANSMISSION
OF BOVINE LEUKEMIA VIRUS INFECTION

by

Mark Cy Thurmond

May 1982

Chairman: Michael Burridge
Major Department: Animal Science

A 27-month study examined 473 dairy cattle for associa-

tions between bovine leukemia virus (BLV) infection and host

and environmental factors. Cattle sera were tested at

monthly intervals for BLV antibodies by agar-gel immuno-

diffusion using the glycoprotein-51 antigen. A model of BLV

colostral antibody decay in 130 calves predicted infection

in calves less than six months of age and estimated anti-

body half-life to be 27.1 1.2 days. Colostral antibody

decay did not differ between BLV-infected and noninfected

calves for slope (p= 0.45) or intercept (p= 0.43). By 95

days of age, 50% of the calves had no detectable BLV

colostral antibodies.

Of 125 calves born to BLV-infected cows and followed

for at least four months, eight (6.4%) had precolostral BLV

antibodies, as determined by radioimmunoassay using the

glycoprotein-51 antigen. In utero infection withBLV was

viii








not associated with dam age (p= 0.86), dam parity (p =0.83),

breed (p= 0.66), sex (p= 0.11), or stage of gestation in

which the dam was infected (p= 0.50). Calves infected in

utero did not pose an increased risk of infection to calves

penned next to them (p = 0.61).

Prevalence rates of infection were 9%, 16%, and 63% at

6, 16, and 27 months of age, respectively. Age-specific

rates of infection were not associated with dam age (p =

0.79), dam parity (p= 0.75), dam BLV-status (p= 0.46), breed

(p= 0.86), or BLV-status of colostrum consumed (p= 0.50).

An algorithm was described which allocated probabili-

ties of infection to locations occupied by an animal prior

to detection of infection. Small calf pastures were associ-

ated with less infection than was the calf barn (p < 0.05).

No less infection was associated with individual outdoor

calf pens compared to contiguous indoor pens (p> 0.05).

Risk of infection associated with the dry herd was five

times that for heifer pastures (p< 0.0001) and accounted

24 infections per 100 heifers per 100 days at risk.

Vaccination for infectious diseases was not associ-

ated with increased BLV infection (p= 0.33). Infection

rates were not associated with month of birth (p= 0.24) or

with season of potential arthropod vectors (p= 0.20).

Heifer infection was likely to occur in late winter or

spring (p = 0.01).













CHAPTER I
INTRODUCTION


Bovine leukemia virus (BLV) has been shown to be the

causative agent of enzootic bovine leukosis, a neoplastic

disease of cattle (Callahan et al., 1976; Kettmann et al.,

1976; Miller et al., 1969). Bovine leukosis is believed to

have spread to western European countries from the Baltic

region during World War I (Bendixen, 1965). Following

World War II, efforts were undertaken in some European

countries to reduce the tumor incidence rate through hemato-

logic examinations for persistent lymphocytosis, a phenomenon

associated with bovine lymphosarcoma (Bendixen, 1965).

After discovery of BLV, and subsequent development and use

of serologic methods for mass screening (Hoff-Jorgensen et

al., 1978; Miller et al., 1969; Miller and Van Der Maaten,

1976a; Onuma et al., 1975; Schmidt et al., 1978), eradica-

tion of enzootic bovine leukosis progressed rapidly (Bause

et al., 1978; Mammerickx et al., 1978a; Straub, 1978b).

In order to preserve gains made in these programs,

restrictions were placed on BLV-seropositive cattle and on

semen entering countries either free from BLV or with BLV

control programs (Miller, 1980). Such restrictions have

placed an economic burden on the cattle export markets of

the United States (Mix, 1979). Because of the high genetic








quality of American cattle, eradication or control of BLV

infection using European methods of test and slaughter

would not be a pragmatic alternative for the American pro-

ducer. Interest, therefore, has focused on prevention of

transmission and test and segregation within a herd (Miller

and Van Der Maaten, 1978a).

A prerequisite to control of BLV in a herd is a clear

understanding of natural transmission of infection from

fetal life to adulthood or to the age at which heifers

would move to export markets. Several constraints make the

study of natural transmission patterns difficult and may

explain the lack of reports of long-term prospective studies

in the literature. A major obstacle is the necessity for a

large sample of animals to be tested at close intervals

over a long time period. At the same time changes in man-

agement or environmental factors must be recorded.

The device used to measure infection must be sensitive,

specific, inexpensive, simple, and meet specifications of

other programs. This necessitates the use of agar-gel im-

munodiffusion because it fulfills the above conditions

(Miller, 1980). Definition of infection by a serologic

test, however, has important limitations. For instance,

discrimination has not been made between colostral anti-

bodies and infection-induced antibodies in calves less

than six to seven months of age which consumed colostrum

from a BLV-infected cow (Ferrer et al., 1977b). Another

problem in defining infection is that seroconversion may








lag behind BLV infection by as much as two to three months

(Mammerickx et al., 1980; Straub, 1978b; Van Der Maaten and

Miller, 1978b, 1978c).

These constraints are not unique to the study of the

epidemiology of BLV transmission. It is important, there-

fore, that designs for the study and eventual control of

BLV be generally applicable to the study of other diseases

and infections.

Examination of risks of BLV infection in a large cattle

population over a 27-month period is presented here as a

logical progression from the fetal environment to adult-

hood. Detection of BLV infection based on serologic cri-

teria is used as a proxy for infection. The intent is not

to attempt statements about specific routes of BLV infec-

tion, but to describe temporal and spatial patterns of

natural infection observed in animals studied. Furthermore,

factors possibly associated with deviations in those pat-

terns will be examined using existing analytic methods in

a framework applicable to other diseases. In addition, new

techniques are presented which improve the efficiency of a

serologically-based diagnosis.














CHAPTER II
LITERATURE REVIEW


Bovine Leukemia Virus Infection


Clinical Appearance


Manifestations of infection with BLV vary from no

signs to persistent lymphocytosis or to lymphosarcoma

(Abramova et al., 1974; Grimshaw et al., 1979; Kenyon and

Piper, 1977; Kumar et al., 1978; Sorenson, 1979; Stober,

1968). Clinical signs of tumor involvement usually are

seen in cattle over five years of age and are referable to

the organ system involved (Abramova et al., 1974, Grimshaw

et al., 1979; Sorenson, 1979; Stober, 1968).

Sporadic bovine leukosis (i.e., juvenile, thymic, or

cutaneous leukosis) is not associated with BLV infection

(Bundza et al., 1980; Chander et al., 1977; Onuma, 1978;

Onuma et al., 1979; Richards et al., 1981; Straub and

Weiland, 1977).

In the absence of tumor involvement, BLV-infected

animals do not appear to suffer production losses (Langston

et al., 1978).


Distribution


Bovine leukemia virus infection is a ubiquitous infection

throughout the world (Burny et al., 1980; Burridge et al.,





5


1981). A survey of cattle in the state of Florida recently

estimated the infection rate of BLV in dairy cattle to be

48% (Burridge et al., 1981).


Bovine Leukemia Virus


Discovery of BLV was made following phytohemagglutinin-

stimulation of lymphocytes from cattle with lymphosarcoma

(Miller et al., 1969). The virus is classified as a single-

stranded RNA retrovirus (Burny et al., 1980). It is spheri-

cal in shape with a diameter of 60-125 nm (Calafat et al.,

1974; Calafat and Ressang, 1977a, 1977b; Dutta et al.,

1970; Miller et al., 1969).

Several viral proteins have been described. There are

at least two glycoproteins, gp-30 (Dietzschold et al.,

1978) and gp-51 (Onuma et al., 1975), which constitute the

outer shell of BLV (Burny et al., 1980; Devare and

Stephenson, 1977; Driscoll et al., 1977). An ether-

resistant protein constitutes the internal or core anti-

gen, known as p-24 (Gilden et al., 1975; McDonald and

Ferrer, 1976; Miller and Olson, 1972). The BLV genome

codes for a reverse transcriptase which has a unique re-
++
quirement for Mg (Dietzschold et al., 1978; Gilden et

al., 1975; Graves et al., 1977; Kettmann et al., 1976).

Six mutant strains of BLV have been investigated recently

(Couez et al., 1981; Kettmann et al., 1981).

Several investigators have identified BLV as a C-type

virus (Burny et al., 1980; Dutta et al., 1970; Ferrer et al.,








1971; Kawakami et al., 1970; Mussgay et al., 1977; Stock

and Ferrer, 1972; Van Der Maaten et al., 1974; Weiland

and Ueberschar, 1976). Others have been reluctant to de-

scribe BLV as a B- or C-type virus since immature viruses

are rarely found outside the cell (Calafat et al., 1974;

Calafat and Ressang, 1977a, 1977b; Dekegel et al., 1977).

Comparisons of BLV with other retroviruses or onco-

viruses by molecular hybridization have shown that BLV is

biochemically distinct from Friend mouse leukemia virus and

visna maedi virus (Kaaden et al., 1977), Rauscher leukemia

virus (Kettmann et al., 1975, 1976), simian sarcoma (wooly

monkey) virus, murine sarcoma virus, feline sarcoma virus,

and feline leukemia virus (Kettmann et al., 1975, 1977).

Other studies have demonstrated a lack of cross-reactivity

between proteins of BLV and Mason Pfizer monkey virus

(McDonald and Ferrer, 1976; McDonald et al, 1976), and

bovine syncytia virus (McDonald et al., 1976).


Pathogenesis


Tissues Involved


Replication of BLV occurs mainly in B-lymphocytes

(Kenyon and Piper, 1977; Paul et al., 1977), but an associa-

tion with T-lymphocytes also has been reported (Takashima

et al., 1977). Further support for B-cell involvement was

found in the expansion of the B-cell population in BLV-

infected cattle (Kenyon and Piper, 1977; Kumar et al.,

1978).








Following subcutaneous inoculation of leukocytes from

a BLV-infected steer, BLV was isolated from the spleen

after eight days, from leukocytes after 14 days, and oc-

casionally from prescapular lymph nodes thereafter (Van Der

Maaten and Miller, 1978b). In that study, BLV could be

isolated from lymphocytes two to three weeks before a de-

tectable serologic response, and virus was not isolated

from the thymus. As few as 2500 washed lymphocytes from an

infected steer have been able to transmit BLV infection to

susceptible calves (Van Der Maaten and Miller, 1978c).


Integration of BLV in the Host Cell Genome


Results of studies using BLV-specific DNA probes sug-

gest that BLV is an exogenous virus (Callahan et al., 1976;

Deschamps et al., 1981; Kettmann et al., 1976, 1978a, 1978b,

1979a; Kukaine et al., 1979). The DNA from lymphocytes of

BLV-infected cattle has viral sequences that cannot be

identified in the DNA from lymphocytes of noninfected cat-

tle (Callahan et al., 1976; Kettman et al., 1976), or in

normal cell DNA from BLV-infected cows (Kettmann et al.,

1978a).

The BLV provirus is integrated in several sites of

the lymphocyte DNA in cattle with persistent lymphocytosis,

but in only one or a few sites in the DNA of cells of

lymph node tumors (Kettmann et al., 1979a, 1980a, 1980b).

Less than 5% of peripheral lymphocytes in asymptomatic,

infected cattle contain the provirus, whereas up to 33% of








the circulating lymphocytes in cattle with persistent

lymphocytosis contain the provirus (Kettmann et al., 1980b).


Seroconversion Period


Seroconversion following infection with BLV has been

found to occur between two and seven weeks in cattle ex-

perimentally inoculated (Mammerickx et al., 1980; Van Der

Maaten and Miller, 1978a, 1978b). Half of the animals in

these studies had seroconverted by five weeks postinocula-

tion. The seroconversion period was similar for sheep

experimentally inoculated by the intradermal route, oral

route, or by BLV-carrying tabanid flies (Gentile and Rutili,

1978; Mammerickx et al., 1980; Ohshima et al., 1981). The

seroconversion period for animals naturally infected is

considered to be less than three months (Straub, 1978b),

and the pattern of seroconversion is believed to be similar

to that for experimentally infected animals (Van Der Maaten

and Miller, 1978b).


Transmission Via Excretions and Secretions


It is well documented that BLV can be experimentally

transmitted to cattle via blood (Mammerickx et al., 1980;

Van Der Maaten et al., 1981a) and lymphocytes (Miller and

Van Der Maaten, 1978b; Van Der Maaten and Miller, 1978a,

1978b) from infected animals. The virus has been demon-

strated in saliva but not in prostatic fluid or feces of

infected cattle (Ressang et al., 1980). The p-24 antigen








of BLV has been found'in urine of naturally infected

animals (Gupta and Ferrer, 1980).

Semen collected by manual massage from a BLV-infected

bull transmitted BLV infection to susceptible sheep (Lucas

et al., 1980). Another study failed to demonstrate BLV in

semen collected from BLV-infected bulls following normal

ejaculation (Miller and Van Der Maaten, 1979).


Serology


Several serologic tests for the detection of BLV have

been described for both the gp-51 and the p-24 antigen

(Burny et al., 1980). Agar-gel immunodiffusion using gp-51

has been recommended for use by member countries of the

European Economic Community (Kaaden and Stephenson, 1978),

because of its high sensitivity, simplicity, and low cost

(Miller, 1980). Recently a radioimmunoassay procedure

was described using gp-51 (Bex et al., 1979). This test

may be the most sensitive one presently available (Miller

et al., 1981).


Factors Examined for Associations with Bovine
Leukemia Virus Infection


Genetic Susceptibility


A genetic predisposition to enzootic bovine leukosis

and bovine lymphosarcoma was suspected before discovery of

BLV. Leukosis was observed more frequently in daughters

of affected cows than in daughters of unaffected cows








(Bendixen, 1965; Larson et al., 1970). Pedigree studies of

lymphosarcoma found clustering of cases by sire and/or dam

families (Crowshaw et al., 1963; Cypess et al., 1974;

Marshak et al., 1962). It also was observed that herds

which were inbred experienced higher rates of leukosis and

lymphosarcoma than did noninbred herds (Abt, 1968; Laktionov

and Nakhmanson, 1972), but purebred herds were found to

have lower rates of leukosis than nonpurebred herds

(Anderson et al., 1971).

One study estimated the heritability of susceptibility

to BLV infection to be 0.44 0.22 (Burridge et al., 1979).

A study of lymphosarcoma, however, was not able to associate

the disease with serologically defined antigens controlled

by the BoLA-A locus (Takashima and Olson, 1978).


Parental Infection with Bovine Leukemia Virus


The effect of BLV infection of the dam on subsequent

BLV infection in the offspring has been examined by several

investigators. In one report, dam status appeared to have

a significant influence on progeny infection (Baumgartener

et al., 1978), but the authors felt that such an effect may

have been due to high prevalence rates in some herds. In a

longitudinal study, no association was found between dam

status and age at which progeny became infected (Olson et

al., 1978). Reports on cross-sectional studies concluded

that presence of BLV antibodies in the dam was not associ-

ated with subsequent progeny infection (Hofirek, 1980;

Valikhov, 1978).








In a large study of progeny from BLV-infected, AI bulls,

offspring from infected sires did not have as high a rate of

subsequent BLV infection as did those from noninfected sires

(Baumgartener et al., 1978).


Sex


Few studies have examined for associations between

BLV infection and sex. Reports in which sex effects were

studied suggested no difference in infection rates between

males and females (Baumgartener et al., 1975; Evermann et

al., 1980).


Breed


It has been reported that many different breeds are

susceptible to BLV infection (Burridge et al., 1981; Marin

et al., 1978). Analysis of data from a survey of Florida

cattle suggested that Jerseys had a higher infection rate

than Holsteins (Burridge et al., 1981). However, a study

within a Florida dairy herd indicated no difference existed

between rates of infections for Jerseys and Holsteins

(Burridge et al., 1979).


Age


Age-specific prevalence rates of BLV infection have

been shown to follow a characteristic sigmoidal curve.

Rates increased linearly from one to four years of age,

after which they plateaued (Burridge et al., 1979, 1981;








Chander et al., 1978; Evermann et al., 1980; Ferrer et al.,

1976; Hofirek, 1980; Mammerickx et al., 1978a, 1978b;

Marin et al., 1978; Olson et al., 1973; Piper et al., 1979).

Peak prevalence rates of infection were observed at four

years of age in beef cattle and at more than nine years of

age in dairy cattle (Burridge et al., 1981). Ages at which

a sharp, linear increase in rates occurred varied from study

to study and from herd to herd. In some herds rates of

infection began to level off at two to four years of age

(Burridge et al., 1979; Olson et al., 1973), while in other

herds rates reached a plateau at four to five years of age

(Chander et al., 1978; Hofirek, 1980; Mammerickx et al.,

1978a, 1978b; Marin et al., 1978).

A few studies have approached age-specific rates of

infection in a longitudinal design using birth cohorts.

Results of one of these investigations showed that animals

of similar ages experienced different rates of infection,

according to the birth cohort (Wilesmith et al., 1980).

In the other study, each new 12-month cohort entered the

herd with a lower prevalence rate than did the previous

cohort. Rates within a cohort did not appear to change as

cattle aged. It was suggested further that higher preval-

ence rates of infection observed in older animals in

cross-sectional studies represented high-rate cohorts

(Huber et al., 1981).








Transmission of Bovine Leukemia Virus Infection


In Utero


Rates of natural in utero infection with BLV have been

reported to range from 3% to 25% (Ferrer et al., 1976,

1977a, 1977b; Piper et al., 1979). Stage of gestation dur-

ing which a dam is experimentally infected has not been

associated with the frequency of infection in progeny (Van

Der Maaten et al., 1981b).


Physical Contact


Close physical contact between infected and susceptible

cattle is believed to be a prerequisite to BLV transmission

(Ferrer and Piper, 1981; Maas-Inderwiesen et al., 1978;

Miller and Van Der Maaten, 1978a; Wilesmith et al., 1980).

Newborn calves were more likely to develop leukosis when

placed in close contact with leukotic cows (Straub, 1971).

Infection rates increased during winter months in one herd

studied, suggesting transmission associated with indoor

housing conditions (Wilesmith et al., 1980). Limiting

physical contact by vacating a stall between animals or by

placing a single fence between animals appeared to retard

transmission of infection (Miller and Van Der Maaten, 1978a).


Arthropod Vectors


Bovine leukemia virus has been isolated from the mid-

gut of horseflies after feeding on a BLV-infected cow








(Bech-Nielsen et al., 1978). In an experimental study,

horsefly transmission of BLV infection to sheep was demon-

strated (Ohshima et al., 1981). It has been suggested

that high rates of infection observed in animals during

summer months support the hypothesis of vector-borne trans-

mission of BLV infection (Bech-Nielsen et al., 1978; Onuma

et al., 1980). Another study, however, observed higher

rates of infection during winter months (Wilesmith et al.,

1980).

Ixodes ricinus ticks have been suggested as a possible

explanation for geographic differences in rates of infec-

tion in Sweden (Hugoson and Brattstrom, 1980).


Aerosol


Intranasal instillation of BLV-infected lymphocytes

produced infection in one of two calves and an aerosol

exposure to BLV-culture fluids produced infection in two of

two calves (Van Der Maaten and Miller, 1978c). Both methods,

however, also exposed the oral cavity and the latter method

exposed the conjunctivae.


Oral


Bovine leukemia virus or BLV-like particles have been

identified in milk and colostrum of BLV-infected cows and

cows with lymphosarcoma (Dutcher et al., 1964; Jensen and

Schidlovsky, 1964; Miller and Van Der Maaten, 1979;

Schulze et al., 1966). Transmission of BLV by the oral








route has been demonstrated by inoculation of leukemic

blood into neonatal lambs (Mammerickx et al., 1976a), by

inoculation of lymphocyte cultures into colostrum-deprived

calves (Miller et al., 1972; Van Der Maaten and Miller,

1978c), and by feeding BLV-infected lymphocytes in colostrum

free of BLV antibodies (Van Der Maaten et al., 1981a).

Oral transmission has not been shown in old lambs (Hoss

and Olson, 1974) or in old calves (Van per Maaten and

Miller, 1978c). Infection did not occur when calves were

fed BLV-infected lymphocytes in colostrum containing BLV

antibodies (Van Der Maaten et al., 1981a). Some studies

concluded that considerable emphasis should be placed on

oral transmission, especially when bloody colostrum or

milk is fed (Parfanovich et al., 1978; Seger and Morgan,

1977). Results of other studies suggest that milk or

colostrum does not constitute a major vehicle for trans-

mission of BLV infection (Ferrer et al., 1976; Ferrer and

Piper, 1978, 1981; Piper et al., 1975, 1979). Pasteuriza-

tion of milk or colostrum for 30 seconds at 600C would

probably inactivate the virus (Baumgartener et al., 1976).


Venereal


One study demonstrated the venereal transmission of

BLV infection after placing BLV-infected lymphocytes in the

cervical canal of susceptible cows (Van Der Maaten and

Miller, 1978c).








Iatrogenic


Intradermal inoculation of BLV has been shown to be a

viable means of transmission (Van Der Maaten and Miller,

1978c). Iatrogenic transmission of BLV following blood

sampling procedures has been suspected (Bause et al.,

1978; Maas-Inderwiesen et al., 1978; Wilesmith, 1979).

Premunization of cattle for babesiosis and other vaccina-

tion procedures also have been incriminated in BLV trans-

mission (Hugoson and Brattstom, 1980; Hugoson et al.,

1968; Marin et al., 1978; Stamatovic and Jonavic, 1968).

However, transmission of BLV to sheep following intradermal

Tb testing has not been demonstrated (Roberts et al., 1981).


Infection in Other Domestic Animals


The possibility for BLV infection in species other

than the bovine was first suggested when bovine leukosis

and later bovine lymphosarcoma were transmitted to sheep

(Olson et al., 1972; Wittmann and Urbaneck, 1969). Ex-

perimental infection with BLV has been confirmed in sheep

(Bansal and Singh, 1980; Bex et al., 1979; Gentile and

Rutili, 1978; Hoss and Olson, 1974; Mammerickx et al.,

1976a, 1976b, 1980, 1981; Olson and Baumgartener, 1978;

Van Der Maaten and Miller, 1976a), in goats (Hoss and

Olson, 1974; Mammerickx et al., 1981; Olson et al., 1981),

and in pigs (Mammerickx et al., 1981). Evidence exists

for experimental BLV infection in rabbits, but not in rats








(Bansal and Singh, 1980), and in guinea pigs (Lussier and

Pavilanis, 1969). Serologic evidence for BLV infection in

chimpanzees has been found (Van Der Maaten and Miller,

1976b). Passage of BLV through cattle, sheep, or goats

did not reduce the infectivity of the virus for cattle,

sheep, goats, or pigs (Mammerickx et al., 1981). Sheep

have not been found to shed BLV and thus may not be a

reservoir (Mammerickx et al., 1976b; Van Der Maaten and

Miller, 1976a).


Reviews


Bovine leukosis, bovine lymphosarcoma, and bovine

leukemia virus infection have been extensively reviewed

(Bendixen, 1965; Burny et al., 1978, 1980; Ferrer, 1977,

1979, 1980a, 1980b; Ferrer et al., 1978, 1979; Hoff-

Jorgensen, 1977; House et al., 1975; Markson, 1979;

Mussgay and Kaaden, 1978; Olson, 1974; Olson et al.,

1970; Reed, 1981; Ruppanner and Paul, 1980; Tyler, 1978;

Van Der Maaten and Miller, 1975).














CHAPTER III
GENERAL MATERIALS AND METHODS


Population Studied


Cattle studied were those in the University of Florida

Dairy Research Unit (DRU) herd. This population was chosen

because it had been characterized previously by a BLV

prevalence rate of 75% (Burridge et al., 1979). Calves

born from July 1, 1979, through June 30, 1981, were fol-

lowed until death, sale, parturition, or September 30, 1981,

whichever occurred first.


Location and Climate


The DRU was located in north-central Florida (latitude

82030' west, longitude 29040' north). It occupied about 450

hectares of reclaimed pine flatwoods 20 km. northwest of the

University of Florida at Gainesville, Florida (APPENDIX A).

The climate was characterized by hot, humid summers and

cool, dry winters (APPENDIX B).


Management Practices


The DRU was a closed herd used as a research facility.

Two 18-month-old heifers, a Jersey (Ml01) and a Holstein

(M121), entered the herd, however, from a commercial dairy








(Bassett's Dairy, Montecello, FL) on May 5, 1980. Both were

negative for BLV antibodies when they entered the herd. The

Jersey had BLV antibodies by April 25, 1981, and the Hol-

stein remained serologically negative through September 26,

1981.

Approximately 200 purebred cows were milked, 1/3 of

which were Jerseys and 2/3 Holsteins. Cattle were allowed

to.graze, but it was necessary to supplement rations with

corn silage; corn, sorghum, ryegrass, or alfalfa greenchop;

and concentrates.

Cattle were bred artificially using commercially avail-

able frozen semen. Some semen was used, however, from

young Jersey control sires raised at the DRU. Calving

season ranged from June through December (APPENDIX C).

Calves were born in small pastures (APPENDIX D, Fig. 1) and

remained with their dams for about 12 hours. They then

were placed in either contiguous, wire pens in the calf

barn (APPENDIX D, Fig. 2) or in individual outdoor pens

(APPENDIX D, Fig. 3). Once in pens, they were fasted for

12 to 24 hours, after which time they were fed either

pooled colostrum (obtained from cows one through three days

postpartum) or bulk-tank milk for the next two to three

days. Prior to weaning at about one month of age, calves

were fed bulk-tank milk once a day. Holsteins received

9 lbs. per day and Jerseys 7 lbs. per day. Calves also

were fed concentrates ad libitum from two or three days of

age.








Electric dehorning, ear tagging, and tattooing were

performed during the first month of life. This usually was

not done in a serial fashion from calf to calf at one ses-

sion, but individually, one or two calves per day.

All heifers were vaccinated for brucellosis,a clostridi-
b c
al diseases, and leptospirosis at four months of age

and for infectious bovine rhinotracheitis (IBR),d bovine

virus diarrhea (BVD),d and parainfluenza-3 (PI-3)d at 11

months of age. Brucellosis vaccination was administered

subcutaneously in the neck and other vaccinations intra-

muscularly in the gluteal area. Cattle were vaccinated in

groups using one or two common 18 gauge 1-1/2 inch needles

and a multidose syringe. The order in which cattle were

vaccinated was not recorded.

At the time of brucellosis vaccination, calves were

wormed eitherwith thiabendazolee or levamisole. The

specific type administered to each calf was not recorded.


aStrain 19, Colorado Serum Co., 4950 New York St., Denver, CO.

Siteguard, Clostridium chauvoei, septicum, haemolyticum,
novyii, sordellii, perfringens Type C and D. Jensen-
Salsbery, Kansas City, MO.
c
Novalep GHP, Jensen-Salsbery, Kansas City, MO.

RESBO 3, Norden Laboratories Inc., Lincoln, NE.

eOmnizole (paste), Merck Animal Health Division, Merck
& Co., Inc., Rahway, NJ.

Ripercol L, American Cyanamid Co., Princeton, NJ, or
Levasole, Pitman-Moore, Inc., Washington Crossing, NJ.








At two to three months of age, calves were moved from

indoor pens in the calf barn, or from nearby outdoor pens,

to paddocks (APPENDIXD, Fig. 4) or to small pastures (0.3

to 0.6 ha.) (APPENDIX D, Fig. 5). At about 10 months of

age, they were moved to larger pastures (2 to 3 ha.)

(APPENDIX D, Figs. 6 and 7). Cattle in each location were

of similar ages.

Heifers were bred between 13 and 16 months of age,

except during summer months when estrous behavior was less

apparent. At 40-45 days gestation, heifers were placed, for

the first time, with adult cattle in the dry herd. For

heifers under study, this began in early January, 1981.

Holstein heifers were removed from the dry herd on May 1,

1981, and placed in pastures holding only bred Holstein

heifers. Jersey heifers continued to be placed in the dry

herd and remained there until shortly before calving.

Most bull calves were sold a few days after birth, al-

though some were retained for veal studies or semen collec-

tion. Management of heifers was similar to that practiced

on most commercial dairies. Heifers usually were not used

in experimental studies until after freshening.

Fly control was practiced sporadically two or three

times during summer months. Lactating cows were hand-

dusted with a commercial insecticide,a and fly baitb was


aMarlate 50, E. I. DuPont de Nemoud and Co., Inc.,
Wilmington, DE.
Golden Malrin, Starbar Division of Zoecon Corp., 12200
Denton Dr., Dallas, TX.








scattered in the calf barn a few times during peak calf

density in the fall. Pastured heifers were not treated

for flies. Most flies observed in the calf barn were

Musca domestic feeding on decaying grain and soured milk.

Pastured cattle were bothered by large numbers of Haematobia

irritans and Stomoxys calcitrans and some tabanidae. No

ticks or lice were observed during the 27-month study.


Sampling Design


Precolostral blood samples were drawn on nearly all

calves born alive between July 1, 1979, and September 30,

1980. To increase the chance of obtaining precolostral

samples, udder bags were placed on cows about one week

prior to calving (APPENDIX D, Fig. 1). This prevented the

calf from nursing until a blood sample could be drawn. In

order to reduce the period of colostrum deprivation, re-

search field personnel were notified by telephone as soon

as a cow calved. This procedure was instituted in December

1979, and calves born after this time were fed 1-2 liters

of colostrum from their own dam within one hour following

birth. After feeding, the navel was washed with a solution

of 3% Lugol's iodine. Through December 1979, calves were

bled precolostrally, at one week of age, and then at three-

month intervals. After December 1979, calves were bled

precolostrally, at two to three days of age, and then at


aNumbers C4591N-C4593N, Nasco, Fort Atkinson, WI.








monthly intervals beginning some time during the first month

of age. Calves born between September 30, 1980, and June 30,

1981, were not bled precolostrally, but were bled at monthly

intervals beginning sometime during the first month of age.

Calves born after June 30, 1981, were not included in the

study. Cows were bled at two, five, and eight months of

gestation, at parturition, and at one month postpartum.

All blood samples were collected from either the jugular or

intercoccygeal vein using a sterile 20 gauge 1-1/2 inch

needle and Vacutainer tube.b


Demographic Information


The following information was obtained for each calf:

BLV status of dam, age of dam, parity of dam, breed, sex,

birth date, sale date, death date, or freshening date.

Locations and inclusive dates of occupation in pens and

pastures were recorded for all cattle as long as they were

followed. As soon as heifers began entering the dry herd,

all cattle in that group were sampled monthly to determine

the BLV status of animals exposed to heifers being studied.

No interventions were made in routine management of calves

or heifers except for colostrum feeding, navel washing, and

monthly mustering and bleeding.



aNo. 5746, Becton-Dickinson and Co., Rutherford, NJ.

bNo. 6512, Becton-Dickinson and Co., Rutherford, NJ.








Serology


Serum samples were tested for presence of antibodies

to BLV glycoprotein-51 antigen (gp-51)a using agar-gel im-

munodiffusion (AGID), as previously described (Burridge

et al., 1979). Gel plates were incubated at 24-27 C in an

humidified chamber for 48 hours before being read with the
b
aid of a direct light beam. Formation of precipitation

lines of identity with positive control sera indicated

presence of BLV antibodies (APPENDIX E). Serial two-fold

dilutions using phosphate buffered saline c were made of

all positive sera and then these dilutions were retested to

determine end-point titers.

All precolostral sera from calves lost to follow-up

before four months of age and negative on AGID were re-

tested using a radioimmunoassay (RIA) procedure with gp-51

(Bex et al., 1979).d Samples precipitating more than 15%

of labeled antigen were considered positive for BLV anti-

bodies. Persistence of antibodies or an increase in BLV

antibody titer was considered evidence of BLV infection.

Precolostral sera from calves with evidence of BLV infec-

tion at some later date were retested by RIA.


aAntigen supplied in the Leukassay-B kit, Pitman-Moore,
Inc., Washington Crossing, NJ, and by Dr. J. Miller, USDA,
Ames, IA.
bModel 651, American Optical Corp., Buffalo, NY.

cDulbecco's formula, Flow Laboratories, Inc., McLean, VA.

Performed by Dr. M. J. Schmerr, USDA, Ames, IA.








Other Species Examined


The DRU maintained between six and eight sheep and

goats during the 27-month study. These animals were kept

in a small pasture, separated from any cattle under study

by at least two fences. Tests for presence of antibodies

to BLV were negative for all sheep and goats in the fall of

1980 and 1981.

Several cats also inhabited the DRU during the study

period. Three of the tamer cats were bled in October 1981,

and no detectable BLV antibodies were found.


Diseases or Conditions Observed


During the 27-month study, lymphosarcoma was diagnosed

in two cows following postmortem examination. Both were

Jerseys, one six years old and the other five years old.

Although no health records were kept, nearly all neo-

natal calves experienced at least one episode of diarrhea

and bronchopneumonia, and several died. According to clini-

cal and pathological reports, a common cause of death,

particularly prior to December 1979, was septicemia result-

ing from omphalophlebitis and/or hypogammaglobulinemia.

Chronic dysentery was prevalent among calves two to six

months of age. This was probably due, at least in part, to

coccidia and trichostrongyles, as suggested by oocysts and

eggs found on fecal flotation. Many calves in this age

group, particularly bull calves in nutrition trials, were








quite cachectic. Heifers older than six months appeared

less affected.


Data Collection and Computer Programs


Data were transcribed onto computer sheets from which

IBM cards were punched. Files were maintained on tape at

the Northeast Regional Data Center (NERDC), University of

Florida, Gainesville, Florida. Computer systems available

through NERDC for statistical analysis were the Statistical

Analysis System (SAS) version 79.5,a Biomedical Computer

Programs (BMDP), and the McGill University System for

Interacting Computing (MUSIC) version 4.1, 1978.

aSAS User's Guide, SAS Institute Inc., Raleigh, NC.

bBMDP, P-series, University of California Press, Berkeley,
1979.














CHAPTER IV
IN UTERO TRANSMISSION OF BOVINE LEUKEMIA VIRUS


Introduction


Since BLV is currently considered an exogenous virus

(Callahan et al., 1976; Kettmann et al., 1976, 1978a,

1978b, 1979a, 1979b; Kukaine et al., 1979) and there is

no evidence for natural transmission of BLV via semen

(Baumgartener et al., 1978; Miller and Van Der Maaten,

1979; Ressang et al., 1980), prenatal infection is most

likely a consequence of in utero transmission. Suggested

rates for in utero transmission of BLV infection have ranged

from 3% to 25% (Ferrer et al., 1976, 1977a, 1977b; Piper

et al., 1979). Highest rates were observed, however, in

an inbred herd in which selection for bovine leukemia had

been practiced (Piper et al., 1979). The BLV status of the

dams was not stated in some reports (Ferrer et al., 1976,

1977a, 1977b); therefore, rates could have been higher

had they been stated correctly in terms of calves born to

infected cows.

It is not known what factors, if any, predispose a

fetus to infection with BLV. Stage of gestation in which

the dam was infected has not been associated with fetal

infection (Van Der Maaten et al., 1981b). If predisposing








factors are present, calves and/or dams with the related

characteristic could be segregated, thus reducing post-

natal transmission. Otherwise, efforts could be focused on

other aspects of transmission control.

The purpose of this chapter is to describe observed

rates of natural precolostral antibodies to BLV in a large

sample of random-bred calves and to examine for associa-

tions between those rates and certain characteristics of

the calves and their dams.


Materials and Methods


Data Analyzed


Calves examined were those born to BLV-infected dams

and bled precolostrally. A BLV-infected dam was defined as

one which had BLV antibodies up to one month postpartum.

Calves were divided into two groups: (1) those post-

colostrally positive for BLV antibodies and followed for

four months or more, or postcolostrally negative for BLV

antibodies and followed for one month or more, and (2) those

with postcolostral BLV antibodies and not followed for four

months. A positive precolostral sample was considered

invalid, if, after following the calf for four months or

more, there was no evidence for BLV infection. Evidence

for BLV infection was based on a rising antibody titer

during the first six months of age, on observation of titers

outside the 95% prediction level of decay of BLV colostral








antibodies (CHAPTER V), or on persistence of BLV anti-

bodies beyond six months of age.


Analysis


Rates of precolostral antibodies in both groups of

calves were examined for associations with breed and sex of

calf. Analyses were performed using the FUNCAT program, a

procedure for analysis of categorical data (Grizzle et al.,

1969) offered by SAS. The model was presence (or absence)

of precolostral BLV antibodies = breed + sex + breed x sex.

The response function was the difference between the pro-

portion of calves with and the proportion without pre-

colostral antibodies to BLV, or, as indicated by SAS, 1 -1.

Differences in age and parity distributions for dams

of calves with precolostral antibodies and dams of calves

without precolostral antibodies were examined using the

NPAR1WAY program of SAS, a two-sample Wilcoxon Rank Sums

test for nonnormal distributions. Fisher's exact test,

from the STATPAK subsystem of MUSIC, was used to calculate

the probability of association between the stage of gesta-

tion of seroconversion to BLV by the dam and occurrence of

precolostral antibodies in calves followed four months or

more.


Results


Of 346 calves born during the period July 1, 1979,

through September 30, 1980, 280 calves were bled








precolostrally and, of those, 223 were from BLV-infected

dams. Because many calves were sold or were not followed

for more than a few months, only 125 calves were born from

BLV-positive cows, bled precolostrally, and followed for

four months or more (Table IV-1). Eight (6.4%) of these

calves had precolostral antibodies and antibodies persist-

ing beyond six months of age (Table IV-1, IV-2). In the

group of 223 calves, 18 (8.1%) had detectable precolostral

antibodies (Table IV-1).

Precolostral antibodies were detected with similar

frequency in Jersey and Holstein calves, both in the fol-

lowed group (p= 0.66) and for all calves (p= 0.80) (Table

IV-3). When all calves were examined, males showed a

significantly higher rate of precolostral antibodies than

did heifers (p=0.04). There was no such association in

the 125 calves followed (p= 0.11) (Table IV-3). No sig-

nificant interactions between breed and sex were detected

for either the group followed (p=0.91) or for all calves

(p =0.64) (Table IV-3).

No statistical differences were detected between dis-

tributions of age (p= 0.86) or parity (p=0.83) for dams

having calves with precolostral antibodies and for dams

having calves without detectable precolostral antibodies

(Table IV-4). Complete serologic records were available

for 76 cows seroconverting before the second month of ges-

tation and for 14 cows seroconverting after the second

month. Those seroconverting after the first trimester of








gestation showed no more tendency to have a calf with pre-

colostral antibodies to BLV than did cows seroconverting

before the first trimester (exact p= 0.50) (Table IV-5).


Discussion


The ruminant fetus may be particularly susceptible to

infection because (1) syndesmochorial placentation does not

allow transfer of maternal antibodies to the fetus; (2) the

fetal immune system is not fully functional; and (3) micro-

bial activity can take place in fetal cells (Osburn, 1981).

Since placentation restricts passage of antibodies to the

fetus, presence of fetal immunoglobulins is indicative of

infection by, or exposure to, an antigen or of placental

leakage of globulins (Brambell, 1970; Husband et al., 1972).

Although no estimates are available for frequency of

placental leaks, such events are believed to be rare

(Brambell, 1970). This has been confirmed by several

studies of in utero infection based on fetal infection and

fetal or precolostral serology (Braun et al., 1973; Dunne

et al., 1973; Fennestad and Borg-Petersen, 1962; Gibson

and Zemjanis, 1973; Horner et al., 1973; Kniazeff et al.,

1967; Osburn and Hoskins, 1971; Osburn et al., 1974;

Van Der Maaten et al., 1981b).

The main difficulty when studying in utero infection

as it occurs naturally in a population, using serologic

detection, is one of logistics. Efforts should be made to

sample the calf as soon after birth as possible and before








it nurses. For this reason, cows were fitted with udder

bags a week or two before their due-date. However, prior

to December 1979, research personnel were lax about udder

bag procedures and precolostral sampling. As a result,

some calves could have sucked BLV-positive cows without

udder bags. Precolostral samples could be partially veri-

fied, however, by following calves to determine if they

became serologically negative. For purposes of analysis,

two groups of calves were described based on confidence in

precolostral samples. A follow-up time of four months was

selected because 80% of calves consuming colostrum contain-

ing BLV antibodies were negative by 120 days of age (CHAPTER

V),and prediction of infected calves, therefore, could be

made with confidence.

Radioimmunoassay using gp-51 antigen has been shown

to be a highly sensitive test of BLV antibodies and may

detect infected animals up to 10 days sooner than AGID

(Miller et al., 1981). After screening with AGID, negative

sera were retested by RIA to identify calves infected in

late gestation. Additional calves identified as precolos-

trally seropositive by RIA may have consumed colostrum, as

previously mentioned. More confidence, therefore, should

be placed on the precolostral antibody rate of 6.4% than on

that of 8.1% because of these logistical problems.

Since reported in utero infection rates of 10% or

more may have counted calves born to negative dams, those

figures represent minimal rates for calves born to infected








dams. In addition, syncytium induction assay, virus neu-

tralization, and/or immunofluorescence assay were used in

those studies to detect BLV or BLV antibodies. These tests

may be less sensitive than RIA with gp-51 for detection of

BLV infection (Miller et al., 1981; Van Der Maaten and

Miller, 1977), and, therefore, in utero infection may have

been underestimated further.

The most likely explanation for the discrepancy between

rates observed in this study and those reported in other

studies rests in innate features of the populations ex-

amined. Higher rates (e.g., 14%, 18%, and 25%) were ob-

served in a Jersey herd in which animals had been inbred

and selected for leukemia (Piper et al., 1979). Such high

rates may suggest a weakening of placental integrity due to

inbreeding allowing for passage of maternal blood into the

fetus. In any case, it is unlikely that the higher rates

are representative of in utero infection in a typical dairy

herd.

A rate of 3% was observed in 37 calves from a multiple-

case herd (Ferrer et al., 1976). Again the BLV status of

dams was not reported, and, therefore, rates in calves from

infected cows were possibly higher. Furthermore, caution

should be taken in considering a rate based on only one in-

fected calf from a small sample of 37 calves.

Results of this study indicated that the risk of BLV

transmission did not differ between older, multiparous cows

and younger or primiparous cows. This suggests that








transmission is not a consequence of loss of placental

integrity associated with increasing physiologic age or

pregnancies. In addition, stage of gestation at maternal

infection did not appear to influence fetal infection rates,

in accordance with observations from experimental studies

(Van Der Maaten et al., 1981b).

Reports on studies of breed effects on BLV infection

rates indicate that many breeds are susceptible (Burridge

et al., 1981; Marin et al., 1978). One report concluded

that higher infection rates occurred in Jerseys (Burridge

et al., 1981), but these differences could have been at-

tributable to high rates in particular age cohorts (Huber

et al., 1981; Wilesmith et al., 1980). Furthermore, no

breed effects were found in a previous study at the DRU

(Burridge et al., 1979).

Although fetal sex showed some statistical association

with precolostral antibodies when both groups were combined,

this possibly resulted from less fastidious postnatal

sampling of bull calves. Colostrum may have been consumed

by more bulls than heifers prior to sampling because less

attention is usually paid to postnatal care of bulls.

From a practical standpoint, knowledge of dam age or

parity probably would not assist in control or prediction

of in utero BLV infection. Economic justification for

efforts to control in utero infection seems unlikely with

a rate as low as 6.4%. Even though control may not be





35


possible, awareness of in utero infection is essential

in planning postnatal management of BLV transmission.
















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CHAPTER V
DECAY OF COLOSTRAL ANTIBODIES TO
BOVINE LEUKEMIA VIRUS


Introduction


Before postnatal transmission of BLV can be studied,

criteria for serologic detection of BLV infection must be

established. This is straightforward for an animal which

seroconverts after a period of seronegativity. However,

during the period when colostral antibodies are detectable,

it is difficult to discriminate between infected and non-

infected calves strictly by the presence or absence of anti-

bodies. In order to more accurately define time or place of

infection, it would be helpful to detect infected calves

during the period that colostral antibodies are detectable.

This chapter will describe the decay of colostral BLV

antibodies in noninfected and infected calves and estimate

normal limits of decay in noninfected calves. It is shown

how these normal limits can be used to detect BLV-infected

calves during the first six months of life.


Materials and Methods


Data Analyzed


Titers were analyzed from calves which had colostral

antibodies on at least three observations, followed by no








serologic reaction for at least two months after the last

colostral antibody titer. These calves were assumed not to

be infected with BLV during the period when colostral anti-

bodies were detectable because, had the virus been present,

an active antibody response probably would have been ob-

served within two months after the last detectable colostral

titer (Mammerickx et al., 1980; Van Der Maaten and Miller,

1978b, 1978c). Furthermore, apparently to date, there is

no evidence that the presence of BLV appreciably alters the

rate of decay of colostral antibodies.

Titers also were analyzed from 14 calves which either

had precolostral antibodies that persisted throughout the

study or had antibodies persisting through eight months of

follow-up. These calves were assumed to have been infected

during at least part of the colostral-antibody period.

Only calves with titers which remained the same or declined

from previous levels were included in regression analysis.

All titers from infected calves were included in estimates

of ages at which BLV infection could first be serologically

detected.


Analysis


Titers were analyzed using an estimated weighted re-

gression procedure (Swamy, 1971). All computations were

performed using SAS. A linear regression predicting the

logl0 of the inverse of BLV antibody titer at various ages

was determined by pooling intercepts and slopes from








individual calf least squares regressions. Each vector of

regression coefficients was weighted by the inverse of its

estimated covariance matrix. The mathematical model was


Y = a + bX + u


where Y (dependent variable) was logl0 of the inverse of

the end-point titer, a was the pooled Y intercept, b was

the pooled rate of decay of logl0 inverse titer, X (inde-

pendent variable) was age in days when the titer was ob-

served, and u was random error. Prediction bands (normal

limits) were calculated for the 90%, 95%, and 99% confidence

levels. A zero titer level was set at log10 (0.5) = -0.3.

Half-life of antibodies was estimated by


a.
n log (10 ) a.
l1gl0 1
b.
1
n


where a. and b. were the Y intercept and slope of the es-
1 1
th
timated regression line for the i calf and n = 130 calves.

A randomly selected set of 61 calves was used to ob-

tain preliminary estimates of a and b and normal limits.

The validity of these estimated normal limits of BLV anti-

body decay was tested using the remaining 69 calves as a

validation group. Since approximately 91%, 94%, and 98% of

the observations in the validation group fell within the

90%, 95%, and 99% normal limits established by the first








set of calves, the two sets were combined and a final pre-

diction model was derived based on all 130 calves.

Regression analysis was repeated for 14 infected

calves which had declining titers for at least three ob-

servations beginning at two days of age. Tests of hypothe-

ses of equal intercepts and slopes of colostral decay were

made using large approximate t statistics (Swamy, 1971,

p. 129).


Results


For the 130 noninfected calves, the number of positive

antibody titers per calf ranged from three to eight. One

of these calves had an early titer as high as 1:256. Dura-

tion of colostral-BLV antibody titers ranged from 51 to 187

days with 50% of the calves serologically negative by 95

days of age (Fig. V-l).

The regression equation for all 130 calves was Y = 1.29

- 0.012X. The mean half-life of BLV antibodies was esti-

mated to be 27.1 days 1.2 days. The prediction line

crossed the zero titer level at 136 days of age, while the

90%, 95%, and 99% upper prediction bands crossed at 168,

178, and 200 days of age, respectively (Fig. V-2).

Serologic diagnosis of BLV-infected calves was made

between 2 and 180 days of age using the 90% limit and be-

tween 8 and 206 days of age using the 99% limit (Table V-l).

The regression line of BLV colostral antibody decay

for 14 infected calves was Y = 1.43 0.012X (Fig. V-3).








No differences were found between noninfected calves and

infected calves for slopes (p= 0.45) or intercepts (p=0.43).


Discussion


Examination of individual calf regressions revealed

little deviation from linearity when titers were expressed

on the logl0 scale. The decision to set the level of a

negative titer at log10(0.5) was based on the two-fold

dilution scheme. Extrapolation below a titer of 1:1 can be

made with confidence because there is no reason to suspect

appreciable deviation from exponential decay below the

level detectable by AGID.

Some assumptions for estimated weighted regression

analysis (Swamy, 1971) could not be perfectly met in this

application. The distribution of log10 of inverse titers,

for example, cannot be assumed to be normal, particularly

as calves age, because titer values truncate at zero. Also,

the method of titer measurement results in a discrete de-

pendent variable which would not have an exact normal dis-

tribution. It is likely that with a sample of 130 calves

violations of these assumptions are not critical. Never-

theless, 69 calves were assigned randomly to a validation

set to test validity of the 90%, 95%, and 99% normal limits.

Since results showed little deviation from expectations, it

can be assumed that these limits were valid. Estimated

weighted least squares analysis was performed instead of

ordinary least squares regression because the assumption of








independence of deviations from overall regression does not

hold when repeated measures are made on each animal (Swamy,

1971).

It is well known that IgG is the major immune globulin

acquired from colostrum by the neonatal calf (Pierce and

Feinstein, 1965; Porter, 1972). These colostrum-derived

immunoglobulins originate from the maternal circulation

where they transfer to colostrum several weeks prior to

parturition (Brandon et al., 1971; Logan et al., 1973;

Smith, 1971; Sullivan et al., 1969). Since AGID using BLV

gp-51 antigen measures IgG1 exclusively (Matthaeus et al.,

1978), decay of colostral BLV antibodies is essentially the

decay of IgG The half-life of IgG1 in the bovine may vary

from 18 to 22.7 days (Brar et al., 1978; Dixon et al., 1952;

Logan et al., 1973; MacDougal and Mulligan, 1969; Smith,

1971). The longer half-life of 27.1 1.2 days found in

this study may have several explanations. Use of larger

and older animals in at least one study may account for a

shorter half-life, since younger and smaller animals may

metabolize IgG1 at a slower rate (Dixon et al., 1952).

Furthermore, the rate of decay of IgG1 may be dependent on

the incidence of diarrhea in calves studied (MacDougal and

Mulligan, 1969).

The 187-day duration of colostral antibody titers to

BLV found in this study was similar to that for infectious

bovine rhinotracheitis (Brar et al., 1978) and bovine viral

diarrhea (Brar et al., 1978; Kahrs et al., 1966; Kendrick








and Franti, 1974). In another study of 21 calves, colostral

antibodies to BLV were detected for only 154 days (Fischer

and Keyserlingk-Eberius (1980). Since AGID has not been

standardized, a discrepancy of this magnitude is not sur-

prising. A lower rate of diarrhea or consumption of a

higher quality or quantity of colostrum also could explain

the longer duration of antibodies found in our study.

The age at which infected calves could be detected was

variable within a given level of normal limits. This is not

unexpected because the critical level at which viral repli-

cation is initiated also is variable and dependent on both

neutralizing antibody and virus concentration (Driscoll

et al., 1977; Straub, 1978b). At the 90% prediction level,

infected calves were identified as early as 2 days and as

late as 180 days of age. At the 99% level, calves were

identified later, from 8 to 206 days of age, but fewer non-

infected calves were misidentified. The sensitivity of

this method varies inversely, whereas specificity varies

directly, with the level of precision (prediction).

Serologic detection of BLV-infected calves during the

period of colostral antibody decay could be used in eradi-

cation or control programs where it would be feasible to

serially dilute serum from calves less than six months of

age. Because typical levels of passive antibodies vary

from region to region and herd to herd (Naylor, 1979), a

decay curve might be defined for noninfected calves which

is characteristic of a herd or region. Since at least three








positive observations are required per animal to estimate

error variance, calves could be bled at weekly intervals

for the first month and at monthly intervals thereafter.

This technique of defining upper limits of colostral

antibodies also could be used in planning strategies for

herd immunization (Kahrs et al., 1966; Kendrick and Franti,

1974). Calves would be vaccinated at the earliest age that

passive antibodies would not interfere with immunization.

Other factors, such as herd disease prevalence, antigen dose

and type, and general health conditions, also should be

considered (Brar et al., 1978; Kahrs et al., 1966; Kendrick

and Franti, 1974; Uhr and Bauman, 1961).

Colostral antibodies decayed at the same rate from the

same level in infected calves as in noninfected calves.

This validated the assumption that presence of BLV did not

alter BLV colostral antibody decay. Use of calves with no

evidence of BLV infection for at least two months beyond

the last colostral titer, therefore, should provide valid

estimates of BLV colostral antibody decay.







Table V-l. Ages at which bovine leukemia virus (BLV) anti-
body titers from BLV-infected calves were above
normal limits of colostral titers of noninfected
calves.


Age (days) at which logl0 1/titer* was first
above the normal limits of
Infected
calf number 90% 95% 99%

J166t 2 2 178
J171 153 153 153
J183$ 151 151 151
Jl94Bt 169 169 169
J200Bt 38 73 206
H875t 180 180 180
H888 154 154 154
H913$ 155 155 155
H938 112 112 167
H949 2 2 8
H955t 160 160 160
H972 137 137 163
H973 67 67 102
H1002Bt 31 31 31
H1038Bt 27 27 144
H1079B 167 167 167

MEAN 106.56 108.75 143.00
SEM 16.54 16.07 13.22

Antibodies measured by agar-gel immunodiffusion using
glycoprotein antigen.

tCalves with precolostral antibodies to BLV.

tCalves with no detectable precolostral antibodies to BLV.

Calves which were not sampled precolostrally.


























100.





,) 80.
U

0
CO
I-
Z 60-






I-




u
> 20.
_j


- -


N
N
N


20 40 60 10 1 l 10 1? 2)t

CALF AGE (DAYS)









Fig. V-1. Percentage of 130 calves with colostral anti-
bodies to bovine leukemia virus (BLV) as a
function of age.





























1. _
-l
UJ-
> L
'- 15
;-

S1.2
LU
Z 0.9

0.6
> 0 0.6

0.3

0.0

-0.3












Fig. V-2.


0 0


--PREDICTION LINE

----99% LIMITS
- 95% LIMITS
...... 90% LIMITS

----- EXTRAPOLATED LINE




iA





AAA AA A A A
N1


0AooAoA '0 00


CALF AGE (DAYS)


Prediction line of the decay of colostral anti-
bodies to bovine leukemia virus (BLV) in 130
calves with no evidence of infection with BLV.
Upper normal limits of the prediction line are
indicated for the 90%, 95%, and 99% confidence
levels; o=values of logl0 1/titer falling
above the 90% normal limit from calves not in-
fected with BLV; A=values of logl0 1/titer from
calves infected with BLV in utero or sometime
prior to six months of age.


















2.7

2.4

2.1

1.8


1.5 -..J4


- PREDICTION LINE

------ EXTRAPOLATED LINE


***


0 a 0


* ^s* *







*** ** *** *
*




, 00 ~


* 0

0 0


20 40 6 0 100 120 1
20 40 60 80 100 10 140


160 1 0 200 210


CALF AGE (DAYS)


Fig. V-3.


Prediction line of the decay of colostral anti-
bodies to bovine leukemia virus (BLV) in 14
calves infected with BLV in utero or sometime
prior to six months of age; =values of log10
1/titer.


2-
LUL

~u


-ow

co _


0.3

0.0

n.I


-I


1.2

0.9

0.6


w.














CHAPTER VI
AGE-SPECIFIC RATES OF DETECTION OF
BOVINE LEUKEMIA VIRUS INFECTION


Introduction


Several factors have been examined individually for

association with prevalence rates of BLV infection in previ-

ous studies. Rates have been reported to be unrelated to

BLV-status of the dam (Hofirek, 1980; Olson et al., 1978;

Valikhov, 1978), consumption of colostrum from BLV-infected

cows (Ferrer et al., 1976; Ferrer and Piper, 1978; Piper

et al., 1975, 1979), or breed (Burridge et al., 1979).

Other studies have suggested that an association exists

between prevalence rates of BLV infection and breed

(Burridge et al., 1981), BLV status of the dam (Baumgartener

et al., 1978), type of colostrum consumed (Seger and Morgan,

1977), and age (Burridge et al., 1979, 1981; Chander et al.,

1978; Evermann et al., 1980; Ferrer et al., 1976; Hofirek,

1980; Huber et al., 1981;Mammerickx et al., 1978a, 1978b;

Marin et al., 1978; Olson et al., 1973; Parfanovich et al.,

1978; Piper et al., 1979). Because age is associated with

BLV prevalence rates, it is important to examine for the

age-specific effects of factors on rates of infection.

The objective of this chapter is to describe age-

specific rates of detection of BLV infection and to test







for differences between rates for cattle identified by

various maternal and management features.


Materials and Methods


Cattle Studied and Criteria for Detection
of BLV Infection


Cattle studied were those described in CHAPTER III.

Calves known to be infected in utero (CHAPTER IV) were ex-

cluded from examination of postnatal infection. Detection

of BLV infection was made when BLV-gp antibodies first ap-

peared following a period of seronegativity. In calves

showing evidence of colostral BLV antibodies, e.g., a declin-

ing titer during the first six months of life, the time at

detection of BLV infection was determined from the model of

colostral antibody decay (CHAPTER V). A calf was detected

as infected when titers first began to increase or when a

titer fell outside the 95% normal limits of colostral anti-

body decay, whichever occurred first. Because the precise

moment of infection could not be measured, the date of de-

tection was used to approximate this time, assuming a uni-

form lag period from infection to detection in all cattle.

A BLV-infected dam was defined as one which had anti-

bodies to BLV during gestation or within one month follow-

ing parturition. A calf was judged to have consumed colostrum

from a BLV-infected cow if the calf had detectable anti-

bodies to BLV in the first postcolostral sample and was








precolostrally negative or if it had postcolostral antibody

titers that declined with age.


Analysis


Data were analyzed using survival regression tech-

niques (Cox, 1972; Taulbee, 1979) available in the PHGLM

program of SAS. Life-table calculations and graphics were

performed using the statistical program P1L of BMDP. Fail-

ure time was defined as the age in days when an animal was

detected as infected with BLV. Censored time was the age

when an animal died, left the herd, calved, or when follow-

up was terminated on September 30, 1981, whichever occurred

first.

The number of cattle at risk of being detected as in-

fected in an age interval ti, defined for graphical purposes

as 30 days, was

c.
1
r. = n.
1 1 2

where n. was the number of animals entering the interval and

c. the number censored in the interval. Conditional prob-

ability of detection in an interval (given that detection

did not occur in the previous interval) was

d.
q 1
Sr.i

where d. was the number detected as infected in the interval.
1
It was assumed that risk of detection remained constant

during an interval. The conditional probability of an








animal not being detected (surviving) in the ith interval

was


pi = 1 q


The cumulative proportion remaining undetected (also known

as cumulative survival or survival rate) to the beginning
th
of the i interval was


Pi = Pi-Pi-


where P =1. Hazard rates (also called failure rates or

force of morbidity) were estimated at interval midpoints

and were defined as the quantity


Xi = 2qi/hi(l+pi)

th
where h. was the width of the i interval. This rate was
1
a linear interpolation estimate based on a life table rep-

resentation of a survival curve.

Standard errors of cumulative survival functions and

hazard rates were calculated as described in the P1L pro-

gram of BMDP for all animals born between July 1979 and

June 30, 1981.

Relationships between hazard rates and other variables

were assessed using the model of the hazard at time t, as

previously described (Cox, 1972) because it adjusts for

censoring in the data. This model is


A(t,zi) = exp(z.i)A(t) ,








where 8 is a vector of unknown parameters and z is the vari-

able under study. The variable z can take on indicator

values (e.g., 1 =positive dam and 0 =negative dam) or

continuous values as in dam age. Implicit in this model

is the assumption that hazard rates for individuals with

different values of the covariate are in constant ratio

over time, regardless of the underlying hazard rate

(Taulbee, 1979). An obvious violation of the proportional

hazards assumption occurs when survival curves cross. This

often is the case with actual data, and it is possible to

examine changes in hazard rates with age using an alterna-

tive function described by Taulbee in which a new variable,

zt, is defined. This allows the ratio of hazard functions

to differ and permits examination for age-by-factor inter-

actions. Conclusions based on this test, however, must be

extremely tentative, since the differences detected as

significant are unknown.

Correlation coefficients were calculated using the

CORR program of SAS to describe relationships between the

various factors investigated. To examine effects of factor

interactions on survival, correlation coefficients were

computed from the variance-covariance matrix of parameter

estimates when all factors were included in the survival

model. High negative correlations between regression pa-

rameters for two factors were interpreted as a reduction in

the effectiveness of one factor in explaining survival when

the role of the other factor on survival became more







important. High positive correlations identified factors

which were jointly effective in explaining survival.

Factors examined were dam age (months), dam parity

(0 =primiparous, 1 multiparouss), dam BLV status when the

animal under study was born (1 =positive, 0=negative),

type of colostrum consumed (1 = from a BLV-infected cow,

0=not from a BLV-infected cow), and breed (1= Hostein,

0 =Jersey).


Results


A total of 473 live calves entered the survival analy-

sis at birth. Of these, nine were detected as infected in

utero (CHAPTER IV) and 54 infected postnatally. Two ani-

mals were followed through 780 days of age (Table VI-1).

Estimates of prevalence rates of infection increased from

2.3% at birth to 63% at 27 months of age (Fig. VI-1).

Survival rates (Fig. VI-1), hazard rates (Fig. VI-2), and

proportion of animals detected as infected for various age

groups (Fig. VI-3) demonstrated four possible age-related

stages of detection. The first stage, prenatal infection,

has been characterized previously (CHAPTER IV). A second

stage appeared as increased hazard rates during the first

six months of life. This was followed by a 10-month period

of sporadic detection. The fourth stage, beginning at 16

months of age, was characterized by sharply increasing

hazard rates of detection through 27 months of age.







Results of statistical analyses using Cox's procedure

are presented in Table VI-2. No differences were found in

hazard rates when variables were examined separately without

the age covariate. However, significant age interactions

were suggested for all factors studied after inclusion of zt

and use of the test by Taulbee (Table VI-2). Graphically,

factor-by-age interactions were indicated for calves con-

suming BLV-positive colostrum (Fig. VI-4), for dam status

(Fig. VI-5), for breed (Fig. VI-6) and for dam parity

(Fig. VI-7). Lower rates of detection of BLV infection

were observed in young calves from infected dams and in

calves consuming colostrum from infected cows. Higher rates

of detection were observed in older Jerseys than in Holsteins

of the same age. Calves born to primiparous dams appeared

to have lower rates of detection through 18 months of age,

after which they began to experience higher rates of detec-

tion until 27 months of age when rates were similar.

Significantly high factor correlations were found be-

tween type of colostrum consumed and dam status (p=0.0001)

and between dam age and parity (p =0.0001), and low, but

significant, correlations were found between dam parity and

dam status (p =0.0001), between colostrum and parity (p=

0.001), and between colostrum and dam age (p =0.001) (Table

VI-3). High, negative correlation coefficients of estimated

parameters of survival were found only for dam age and

parity (r=-0.97) and for colostrum and dam status (r=

-0.86) (Table VI-4).








Discussion


Throughout this study increasing or persisting antibody

titers to BLV, as measured by AGID-gp, were interpreted as

evidence for BLV infection. Because this method indirectly

tests for presence of virus by an immune response, some as-

sumptions regarding sensitivity and specificity of the

diagnostic criteria should be made.

The BLV-gp antigen appears to be unique, since no cross

reactivity with proteins of other oncoviruses or retro-

viruses has been demonstrated (Ferrer, 1972; Ferrer et al.,

1975; Kaaden et al., 1977; McDonald and Ferrer, 1976;

McDonald et al., 1976). A positive serologic response to

BLV-gp, therefore, can be considered specific for BLV.

Comparisons of several serologic tests have demonstrated

that AGID-gp is a relatively sensitive serologic test (Burny

et al., 1980). These results are corroborated by experi-

mental studies in which a serologic response following BLV

inoculation was consistent (Miller et al., 1972; Schmidt

et al., 1976; Van Der Maaten and Miller, 1978b; Van Der

Maaten et al., 1981a) and persistent (Miller and Van Der

Maaten, 1976b). Similarly, BLV has been readily detected

from seropositive but not seronegative animals following

natural infection (Ferrer et al., 1976, 1977a, 1977b;

Olson et al., 1973; Piper et al., 1979).

There is no evidence for recovery from BLV infection.

On the contrary, seropositive cattle older than six months








appear to maintain detectable antibodies throughout life

(Chander et al., 1978; Kaaden et al., 1978; Tabel et al.,

1976). In a study to examine vaccine efficacy, inactivated

BLV produced only a transient serologic response, and virus

was not isolated (Miller and Van Der Maaten, 1978b). In

that study two doses of killed virus were required to induce

a serologic response. This suggests that persistent anti-

body titers only result from active, persistent infection

and that any transient serologic response resulting from

exposure to a killed virus is rare.

Until recently, it could not be stated that absence of

either virus or antibody implied absence of specific BLV

sequences in host cell genomes. Studies now suggest that

such sequences are not to be found in cattle without BLV or

specific BLV antibodies (Callahan et al., 1976; Deschamps

et al., 1981; Kettmann et al., 1976).

A final demonstration of the sensitive nature of AGID

using gp-51 lies in results of BLV-eradication programs

based upon mass screening with this test. Results of these

campaigns indicated that the virus was efficiently removed

from aherd by test-and-slaughter methods (Mammerickx et al.,

1978a; Schmidt et al., 1978, Straub,1978b). If AGID were

not an efficient discriminator of infected and noninfected

cattle, it is unlikely that eradication efforts would have

met with such rapid success. Use of AGID-gp to detect BLV

infection, therefore, is justified, particularly in a design








in which animals can be followed for several months and

persisting titers can be observed.

Survival analysis and life-table methods are well es-

tablished techniques in epidemiology and actuarial science

(Gross and Clark, 1975; Lilienfield, 1976). Recently these

methods have seen increased application in veterinary

epidemiology (Cobo-Abreu et al., 1979; Hird et al., 1975;

Schwabe et al., 1977). Survival analyses are especially

appealing in prospective studies where animals lost to

follow-up can be considered in computations up to the time

of censoring, assuming failure rates similar in censored

and uncensored animals.

Data presented in this study are particularly suitable

for examination by survival methods for two reasons. First-

ly, recovery from BLV infection is unknown and animals can

be defined as truly failed once infection is detected.

This is analogous to death in traditional applications.

Secondly, since these methods incorporate the dimension of

time, either by comparing distributions over time or by

using time as a dependent variable, they are appropriate

in studies of BLV infection because prevalence rates are

known to be associated with age (Burridge et al., 1979,

1981; Chander et al., 1978; Evermann et al., 1980; Ferrer

et al., 1976; Mammerickx et al., 1978a, 1978b; Marin et

al., 1978; Olson et al., 1973; Piper et al., 1979).

Cox's model was used to test estimated parameters of

a survival function where the underlying assumption was








that hazard rates were proportional (Cox, 1972; Taulbee,

1979). The model tends to force nonparallel curves to a

parallel model. Thus, interaction, characterized by cross-

ing or bellying curves, could not be examined. Inclusion

of the zt variable removes dependence on proportionality and

allows for tests of interactions with age (Taulbee, 1979).

Estimated age-specific prevalence rates were calculated

as one minus the proportion remaining negative for BLV in-

fection. The prevalence rate estimate for 18-month-old

cattle of 25% was lower than that of 45% described from a

cubic polynomial curve fitted to data collected from the

same herd for the years of 1975 through 1977 (Burridge

et al., 1979). Transmission rates of BLV infection, there-

fore, appeared to have declined over the past four to five

years, at least in animals up to 18 months of age. This

may suggest variations of prevalence rates in yearly birth

cohorts, as found in other prospective studies (Huber et al.,

1981; Wilesmith et al., 1980). In those studies, it was

observed that cattle born in a given year experienced a

different life-time prevalence rate than did animals born

in some other year. Furthermore, the prevalence rate

within a cohort did not change appreciably beyond two

years of age. A similar situation may have occurred in

this herd due to management of Holstein heifers. Prior to

1977, bred Holstein heifers were kept in the dry herd until

shortly before calving. In the past few years, these

heifers have been managed separately from the dry herd,








whenever pasture space permitted, in order to provide them

with a better plane of nutrition. In this study Holstein

heifers were exposed to the dry herd for a relatively short

time, January through April 1981, which could have limited

BLV transmission and resulted in the lower prevalence rates.

Inspection of the overall life table revealed heavy

censoring during the first two to three months. This was

due to sales of bull calves and to neonatal mortality.

Early postnatal detection of BLV infection, constituting

the second detection phase, could have been represented by

calves infected in utero and not sampled precolostrally or

infected too late in gestation for antibodies to appear by

birth, as previously suggested (Van Der Maaten et al.,

1981b). Evidence that postnatal infection occurred during

this period was demonstrated by detection of infection in

calves born to noninfected dams.

The length of this period of detection would not cor-

respond to the length of an underlying infection period

because of the seroconversion lag time (CHAPTER VIII) and

possible repression of viral expression by colostral anti-

bodies. Inhibition of release of BLV by antibodies has

been demonstrated in vitro (Driscoll et al., 1977) and also

suggested in studies of colostral antibodies (Van Der Maaten

et al., 1981a). Antigenic modulation or inhibition of P

proteins (Sissons and Oldstone, 1980) may explain such a

phenomenon. The process of modulation is believed to

involve a binding of viral glycoprotein on the cell membrane







by circulating antibodies. Glycoprotein surface markers

become masked from recognition by K cells or other cells

invoking an antibody dependent cytotoxic response. A

failure to recognize virus-bearing lymphocytes by the

immune system renders them resistant to immune damage. If

antibodies are removed, for instance through natural at-

trition of gammaglobulins, the lymphocyte would regain the

ability to shed virus. Inhibition of P proteins may also

be involved in repressing virus expression by inhibiting

transcription.

A further delay in detection, beyond the two- to three-

month seroconversion period and one-month sampling interval

could have resulted from early sampling-design flaws. As

much as a two-month delay could have occurred as a result

of the three-month sampling interval used at the beginning

of the study. It is likely, therefore, that infection

represented by this phase of detection occurred in the

first two to three months of life or even prenatally.

Several factors may have contributed to postnatal

transmission in the first two to three months. Calves may

have become infected at parturition when a calf born to an

infected dam ingested maternal blood from uterine or vaginal

tears (Van Der Maaten et al., 1981b). Rates of detection

in calves from infected dams, at least during the first

three months, however, were not different from rates in

calves from noninfected dams. Such a similarity of rates

may be an artifact due to delayed expression of the virus








by colostral antibodies. Consumption of colostrum with

BLV antibodies, therefore, may complicate control efforts

by masking early infection.

Type of calf management also may have influenced BLV

transmission during the first few months of life. Most

calves were placed inside the calf barn where they could

have been exposed to infected calves in adjacent pens.

Transmission may have resulted from ingestion or inhalation

(Van Der Maaten and Miller, 1978c) of saliva (Ressang et al.,

1980), urine (Gupta and Ferrer, 1980), blood (Mammerickx

et al., 1980; Van Der Maaten et al., 1981a), or lymphocytes

(Miller and Van Der Maaten, 1978b; Van Der Maaten and

Miller, 1978b, 1978c, 1981a). Animals were also tattooed

while in the barn, introducing the opportunity for iatro-

genic transmission. Other calves occupied reasonably iso-

lated pens outdoors, and they may not have experienced the

same risks of infection as indoor calves. Risks for animals

in various locations are examined further in CHAPTER VIII.

A third relatively quiescent phase of detection of BLV

infection between 6 and 15 months of age coincided with

movement of animals from densely occupied paddocks to

fields and pastures (APPENDIX D, Fig. 7). It also was noted

that vaccinations for other infectious diseases were given

either shortly before or during this period. Iatrogenic

transmission of BLV, therefore, does not appear to have

been of major importance in transmission because rates of

detection actually declined during this period. A more








detailed examination of detection rates and vaccination pro-

cedures is presented in CHAPTER VII.

A sharp increase in detection rates typified the fourth

and last observed phase which began after 15 months of age.

The only management interventions preceding the increased

rates were insemination and movement of bred heifers to the

dry herd. Infection as a result of close physical contact

has been suggested as the major mode of BLV transmission

(Dechambre et al., 1968; Maas-Inderwiesen et al., 1978;

Straub, 1971, 1978a; Miller and Van Der Maaten, 1978a;

Wilesmith et al., 1980). Other reports mentioned similar

observations or seroconversions following exposure to in-

fected animals (Ferrer et al., 1976; Piper et al., 1979).

However, in our study not all bred heifers entered the dry

herd, permitting a comparison of risks of two types of

heifer management in CHAPTER VIII.

It is not likely that transmission resulted from in-

semination, since the exogenous nature of BLV excludes

transmission via gametes. This has been confirmed by

observational studies which did not find increased infec-

tion rates in animals sired by BLV-infected bulls (Baum-

gartener et al., 1978) and by experimental studies which

failed to transmit BLV with semen from BLV-infected, but

otherwise healthy, bulls (Miller and Van Der Maaten, 1979;

Ressang et al., 1980). Furthermore, the time from breeding

(13-16 months of age) to peak rates of detection (18-21

months of age) was longer than suggested by experimental or








natural transmission studies (Gentile and Rutili, 1978;

Mammerickx et al., 1980; Straub, 1978b; Van Der Maaten and

Miller, 1978a, 1978b). Unfortunately, an effect of in-

semination on transmission could not be examined further

because BLV status of sires was unknown and analysis would

have been confounded by the presence of only bred heifers

in the dry herd.

In the examination for associations between hazard

rates and dam age, dam parity, dam status, breed, and colos-

trum type using Cox's model, no significant main effects

were observed. Results of Taulbee's alternative procedure,

however, suggested significant departures from proportional

hazards. The sizes of the differences detected by this al-

ternative method are not known, and they may be too small

to be of practical importance in the control of BLV in-

fection. Conclusions regarding the practical significance

of interactions, therefore, should be very tentative, but

discussion can be based on inspection of survival curves.

Graphical examination is meaningful because crossing of

survival curves cannot occur without crossing of hazard

curves, thus allowing for visual inspection of factor-by-

age interaction.

Interactions between age and dam status and between

age and colostrum have already been discussed and indicated

that calves which consume colostrum from an infected cow or

which were born to a seropositive dam were protected from

detection but not necessarily infection, at an early age.








These two factors would be expected to have similar curves

because of the high negative correlation of their estimated

survival parameters. Although several factors were sig-

nificantly correlated with each other, only dam parity and

dam age, and dam status and colostrum were correlated when

hazard rates of detection were considered.

An interaction of breed by age was suggested when old

Jersey heifers were observed to have higher rates of detec-

tion than old Holstein heifers, but at young ages curves were

similar. It has been reported that Jerseys have low levels

of circulating gammaglobulins (Logan et al., 1981), but

this would not necessarily explain increased susceptibility

only in old Jersey heifers. A more reasonable explanation

for lower survival rates in old Jersey heifers is that they

remained in the dry herd until shortly before calving.

Holstein heifers, on the other hand, were removed from the

dry herd on about May 1, 1981, and Holsteins bred 45 days

prior to that time were never in the dry herd. The breed-

by-age interaction, therefore, was due most likely to

longer exposure of Jerseys to older, infected cattle in

the dry herd.

There has been no mention made in the literature of

dam parity or dam age effects on subsequent BLV infection

of progeny. Crossing of survival curves of animals from

primiparous and multiparous dams observed in this study

suggests an age-by-parity or age-by-dam age interaction.

Whether the crossing of these curves represents expected





70


variation, especially with small numbers at older ages, or

a real effect cannot be stated. No other explanation can

be provided.












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Table VI-4. Correlation coefficients of estimated parame-
ters of hazard rate functions for the detection
of bovine leukemia virus infection.


Variable

Variable Dam status Dam age Colostrum Breed

Dam parity -0.002 -0.973 0.027 0.087

Dam status -0.027 -0.857 -0.021

Dam age -0.036 -0.052

Colostrum -0.037























CUMULATIVE SURVIVAL

.--- CUMULATIVE PREVALENCE


CA 80-
uJ
I.-


u J
UJ.
Z 60- /




z
>I /
/

20





I I I I I I 1 1 1 1 I I I 1 1 1 I 1 I i
3 6 9 12 15 18 21 24 27
AGE (MONTHS)









Fig. VI-1. Estimated age-specific cumulative survival
(%) and prevalence rate (%) of detection of
bovine leukemia virus infection.






77















1.0-


.9


8-
0o
I.-
U .7-
LU

-" .6-
o
-z .5


.4-
oi u.
0 0
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3 6 9 12 15 18 21 24
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Fig. VI-2. Age-specific hazard rates of detection of
bovine leukemia virus (BLV) infection.


































20


o-15
Ul-

Z 10

Iz
7<
>Z


9 12 15 18
AGE (MONTHS) AT DETECTION


Fig. VI-3.


Age at detection of bovine leukemia virus (BLV)
infection for 63 BLV-infected animals.























1.0 ---- CALVES CONSUMING
BLV- POSITIVE COLOSTRUM
.9 ------------CALVES CONSUMING
S. -------- BLV-NEGATIVE COLOSTRUM

Z .8

u>
^ .7
Z c


0
2 .6















Fig. VI-4. Cumulative proportion of calves consuming colos--
















antibodies remaining undetected for BLV infec-
tio .n.


.3



100 200 300 400 500 600 700 800

AGE (DAYS)











Fig. VI-4. Cumulative proportion of calves consuming colos-
trum with bovine leukemia virus (BLV) antibodies
and of calves not consuming colostrum with BLV
antibodies remaining undetected for BLV infec-
tion.





















CALVES BORN FROM
BLV-INFECTED DAMS

------CALVES BORN FROM
NON-INFECTED DAMS


AGE (DAYS)


Fig. VI-5.


Cumulative proportion of animals from bovine
leukemia virus (BLV)-infected dams and from
noninfected dams remaining undetected for
BLV infection.












































AGE (DAYS)


Fig. VI-6.


Cumulative proportion of Holsteins and Jerseys
remaining undetected for bovine leukemia virus
(BLV) infection.


























BORN TO
PRIMIPAROUS DAMS
9- ----BORN TO
o MULTIPAROUS DAMS
Z
0 .8-


Z .7-




u





I-1 I I I I I I I I I I I-
i&
-02 \







100 200 300 400 500 600 700 800
AGE (DAYS)








Fig. VI-7. Cumulative proportion of animals born to primi-
parous cows and of animals born to multiparous
cows remaining undetected for bovine leukemia
virus (BLV) infection.














CHAPTER VII
SEASONAL PATTERNS OF RATES OF BOVINE LEUKEMIA
VIRUS INFECTION


Introduction


A fundamental consideration in the epidemiology of in-

fectious diseases is the examination for temporal patterns

of occurrence of a disease. Seasonal or secular trends in

incidence rates may suggest modes of transmission, causal

associations, and/or etiologic agents. If, for example, a

hypothesized factor in disease transmission demonstrates

seasonal variability, and a statistically significant season-

al cycle of disease exists in phase with the hypothesized

factor, then supporting evidence favoring involvement of

the factor in transmission has been demonstrated. On the

other hand, if no seasonal occurrence of disease can be

demonstrated, or it is not in phase with that of the factor,

then the hypothesis of factor association should be rejected.

Interest in possible vector-borne transmission of BLV

has arisen from evidence for arthropod involvement in the

spread of another retrovirus, equine infectious anemia virus

(Fischer etal., 1973; Hawkins et al., 1973a, 1973b). Re-

ports based on experimental and observational data have

suggested the involvement of arthropod vectors in BLV trans-

mission (Bech-Nielsen et al., 1978; Ohshima et al., 1981).








Another study, however, revealed higher rates of infection

during winter months, coinciding with crowded, indoor hous-

ing conditions rather than exposure to large numbers of

flies (Wilesmith et al., 1980).

In this chapter, the hypotheses tested are as follows:

(1) age-specific rates of detection of BLV infection do

not differ with respect to month of birth; (2) rates of

detection of BLV infection show no significant seasonal

pattern associated with the seasonal frequency of potential

arthropod vectors; and (3) no other seasonal pattern of

rates of detection exists.


Materials and Methods

Month of Birth


Cox's hazard model described in CHAPTER VI was used to

examine for an association between month of birth and sub-

sequent BLV infection. Month of birth was denoted by z in

the model. Detection of BLV infection was based on cri-

teria presented in CHAPTER VI.


Month of Detection of BLV Infection


Monthly incidence rates of detection of BLV infection

were computed to estimate seasonal patterns of BLV infec-

tion rates. Monthly incidence rates of detection were cal-

culated as the number of animals detected during the month

divided by the number of animals at risk of being detected








in that month. The criteria for an animal to be at risk for

any month of follow-up were (1) the animal must not have

been detected previously; (2) the animal must have been

present for at least half of a month; (3) an animal born in

the last half of a month was considered only in subsequent

months; and (4) an animal remaining undetected for more

than one year would be considered also for each repeated

month. For example, if an animal were present during

January 1980, and January 1981, it would be counted as

two animals-at-risk during the month of January. Those

animals detected as infected during a month also were

counted in the at-risk denominator.

Possible differences between the 12 monthly incidence

rates were examined using a Chi Square test with 11 degrees

of freedom. In order to determine if monthly incidence

,rates followed a simple harmonic trend, a test for goodness-

of-fit of the data to a simple harmonic curve was performed

using a Chi Square statistic, as previously described

(Walter and Elwood, 1975). The test for a simple harmonic

trend of incidence rates, however, could not be pursued
2
because a high Chi Square value (X = 17.5, 0.05 (11)
indicated that these rates were inappropriately described

by a simple harmonic curve.

An alternate, nonparametric approach to the seasonality

of events was used to examine for six-month trends in in-

cidence rates (Hewitt et al., 1971) Rates were computed

only for animals over 12 months of age. The tested








hypothesis stated that six-month cumulative ranks of inci-

dence rates from May through October, the fly season, were

not greater than those for the 11 other six-month periods.

A second hypothesis was tested for no differences in cumu-

lative ranks of incidence rates for any nonspecified six-

month period.


Results


Month of Birth


No significant differences were found between hazard

rates of detection of BLV infection for animals born in

each of the 12 months (p= 0.24). The proportion of animals

infected was highest in animals born in August, September,

and October (Fig. VII-1).


Month of Detection of BLV Infection


No significant differences were found between the 12
2
monthly incidence rates (X(II) = 9.81, 0.4
The numbers of animals detected as BLV infected and at

risk of detection for each of the 27 months of observation

are presented in Table VII-1. Monthly incidence rates of

detection for animals of all ages ranged from 1.1% in

January and April to 3.0% in June (Fig. VII-2). For ani-

mals over 12 months of age, cumulative ranks of monthly

incidence rates between May and October were not signifi-

cantly greater than those for any other six-month period








(p= 0.20) (Table VII-2). Cumulative ranks of monthly in-

cidence rates were highest for the six-month period be-

ginning with March and were lowest for the period beginning

with September. The probability of cumulative ranks was

lowest for the period beginning with March, but this was

not significant without an a priori commitment (p= 0.13).


Discussion


Although no statistical significance could be placed

on differences between birth-cohort hazard rates, calves

born between August and October constituted 65% of the in-

fected animals, even though only 42% of calves were born

during that period (APPENDIX C). This was not surprising

for several reasons. The density was highest during the

period in which these calves were in the calf barn

(CHAPTER III). In a crowded situation, transmission may

occur either by aerosol (Van Der Maaten and Miller, 1978c)

or by contact (Dechambre et al., 1968; Maas-Inderwiesen

et al., 1978; Miller and Van Der Maaten, 1978a; Straub,

1971, 1978a; Wilesmith et al., 1980). Also, since these

animals were the oldest in the study, they had a greater

chance of entering the dry herd where there may have been

an increased risk of infection due to contact with older,

BLV-infected cattle. Calves born during the winter and

spring were too young to be bred and enter the dry herd by

May 1981. The proportion of calves born in the spring and








subsequently becoming infected would be expected to be low

because few cows calved at that time (APPENDIX C).

Two assumptions were made in the analysis of monthly

incidence rates of detection of BLV infection. One was

that animals were considered independent within and among

months followed. This is reasonable because exposure to

a possible BLV-carrying insect and susceptibility to BLV

infection were not likely to be related to any previous

experience.

The other assumption in examination of monthly inci-

dence rates was that any pattern of detection would be

synchronized with that of infection and would consistently

follow infection by two to three months. This assumption

may not be valid for calves less than six months of age.

Infection may occur in utero or shortly before birth but

before acquisition of passive protection from colostral

antibodies. In such cases, detection of infection may not

be made for six months or more because virus repression may

be dependent on both antibody and virus concentration

(Driscoll et al., 1977; Straub, 1978a). It is believed,

however, that viral expression would appear within 12

months of infection (Van Der Maaten et al., 1981a).

Analysis of possible vector transmission also may have

been confounded by calfhood management. Since the calving

season occurred during the summer and early fall, animal

density in the calf barn was highest during late summer and

fall. Seroconversion of animals several months later could








be interpreted as infection resulting from close physical

contact rather than from arthropod vectors. Furthermore,

the risk of infection for calves in the calf barn may not

have been as high as for those over one year of age. Flies

found in the calf barn were not usually the biting type,

and sporadic insect control was practiced, which limited

exposure to potential vectors. Colostral antibodies also

may have provided some resistance to infection from small

doses of virus introduced by an insect (Van Der Maaten

et al., 1981a).

The situation with cattle more than 12 months of age

was quite different. Biting flies were present on these

animals throughout summer months, and no fly control was

practiced. Prevalence rates of infection also were higher

in these animals (CHAPTER VI), increasing the chance that

a fly would first feed on an infected animal. Cattle over

one year of age, therefore, were analyzed separately as they

constituted a more susceptible and exposed population to

possible vector-borne transmission and because infection

was more easily detected and analysis was not confounded

by management factors.

Results of the Chi Square test indicated that there

were no significant differences between monthly incidence

rates. Important seasonal trends, however, may be present

without apparent rate differences between months (Walter

and Elwood, 1975). The method proposed for analysis of

seasonal trends in incidence rates (Edwards, 1961; Walter








and Elwood, 1975) was particularly appealing because season-

al frequencies of potential arthropod vectors in temperate

and subtropical climates generally resemble simple harmonic

curves which peak during summer months (Beck, 1958; Blanton

and Wirth, 1979; Bohart and Washino, 1978; Jones and Anthony,

1964; Khalaf, 1969). Their analysis could not be pursued

because the incidence rates were inappropriately described

by a simple harmonic curve. The goodness-of-fit test in-

dicated that incidence rates did not resemble a simple har-

monic curve and no further tests for significance or maximum

amplitude of a curve should be performed. This analytic

method also could not be used to test rates in older animals

because the recommended sample size is not less than 50

(Walter and Elwood, 1975). Instead, a nonparametric method

appropriate for small samples was used to examine for ex-

cessive rates over six-month periods (Hewitt et al., 1971).

Difficulties with Hewitt's alternative procedure have

been its lack of power and inability to estimate parameters

of an harmonic curve (Walter and Elwood, 1975). In spite

of these restraints and the few infections detected, a

marked tendency for maximum risk of detection of infection

was revealed between March and August (p= 0.13), the six-

month period beginning with March. Had an a priori hypothe-

sis been specified for that particular yearly segment, there

would be reason to believe that an excessive rate of de-

tection had occurred during that period (p= 0.01). This

interval would coincide with infection resulting from








exposure to animals in the dry herd between January and May

1981. If vectors had played a major role in transmission

and assuming peak infection around July, then maximum

cumulative ranks of incidence rates of detection should

have been observed between May and October. This was not

the case, as indicated by acceptance of the hypothesis of

no increase in incidence rates for that six-month period.

Results of this study are consistent with those from

a study in which increased rates of seroconversion were ob-

served after cattle grazed together on summer pastures

(Onuma et al., 1980). In that study, arthropod-borne

transmission could not be examined because analysis would

be confounded by congregation of cattle only during the

vector season. In another study, two groups were compared

for rates of infection during winter and summer months

(Bech-Nielsen et al., 1978). Rates observed for summer

and winter groups, 4/7 and 1/7, respectively, could have

occurred by chance (Fisher's exact p=0.13). A study of

incidence rates of BLV seroconversion in a large dairy

found higher rates in winter and spring, implying trans-

mission associated with crowded housing (Wilesmith et al.,

1980). None of these studies examined monthly rates for a

complete seasonal cycle. Future studies of seasonal patterns

of disease should be based on at least two years of monthly

cohort data in an attempt to remove as much year-effect as

possible.




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EPIDEMIOLOGY OF NATURAL TRANSMISSION
OF BOVINE LEUKEMIA VIRUS INFECTION
BY
MARK CY THURMOND
A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL
FULFILLMENT OF THE REQUIREMENTS FOR
THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
1982

Copyright 1982
by
Mark Cy Thurmond

DEDICATED TO
AUDREY

ACKNOWLEDGEMENTS
Technical assistance with agar-gel immunodiffusion and
animal sampling was provided by Ms. J. Hennemann, Ms. J.
Ring, Mr. C. Maden, Mr. T. O'Donnell, Mr. A. Green, and
Mr. J. Lindsey. Most data management and computer program¬
ming were performed by Ms. J. Galvez and Mr. D. Puhr. Edi¬
torial assistance was provided by Dr. M. Burridge, Dr. P.
Nicoletti, and Dr. C. Wilcox. The typist was Ms. B.
Smerage. The valuable support and discussions offered by
the following people are gratefully acknowledged: Dr. M.
Burridge, Dr. R. Carter, Dr. M. Drost, Dr. C. Franti
(University of California/Davis), Dr. J. Gaskin, Dr. R.
Kahrs, Dr. J. Miller (USDA, Ames, IA), Dr. K. Portier,
Dr. 0. Straub (West Germany), Dr. M. Van Der Maaten (USDA,
Ames, IA), Dr. S. Walter (Yale University), and Dr. C.
Wilcox. Additional thanks is extended to Dr. R. Carter,
Dr. K. Portier, and Dr. C. Wilcox for their interest and
support in statistical designs and analyses. Financial aid
was provided by United States Department of Agriculture
cooperative agreement 58-519B-0-872 and by the Wetterburg
Foundation of Newark, New Jersey.
IV

TABLE OF CONTENTS
PAGE
ACKNOWLEDGEMENTS iv
ABSTRACT viii
CHAPTER
IINTRODUCTION 1
IILITERATURE REVIEW 4
Bovine Leukemia Virus Infection 4
Bovine Leukemia Virus 5
Pathogenesis 6
Transmission Via Excretions and
Secretions 8
Serology 9
Factors Examined for Associations with
Bovine Leukemia Virus Infection .... 9
Transmission of Bovine Leukemia Virus
Infection 13
Infection in Other Domestic Animals. ... 16
Reviews 17
IIIGENERAL MATERIALS AND METHODS 18
Population Studied 18
Location and Climate 18
Management Practices 18
Sampling Design 22
Demographic Information 23
Serology 24
Other Species Examined 25
Diseases or Conditions Observed 25
Data Collection and Computer Programs. . . 26
IVIN UTERO TRANSMISSION OF BOVINE LEUKEMIA
VIRUS 27
Introduction 27
Materials and Methods 28
Results 29
Discussion 31
v

PAGE
V DECAY OF COLOSTRAL ANTIBODIES TO BOVINE
LEUKEMIA VIRUS 41
Introduction 41
Materials and Methods 41
Results 44
Discussion 45
VI AGE-SPECIFIC RATES OF DETECTION OF BOVINE
LEUKEMIA VIRUS INFECTION 53
Introduction 53
Materials and Methods 54
Results 58
Discussion 60
VII SEASONAL PATTERNS OF RATES OF BOVINE
LEUKEMIA VIRUS INFECTION 83
Introduction 83
Materials and Methods 84
Results 86
Discussion 87
VIII SPATIAL PATTERNS OF BOVINE LEUKEMIA VIRUS
INFECTION 98
Introduction 98
Materials and Methods 99
Results 104
Discussion 105
IX IATROGENIC TRANSMISSION OF BOVINE LEUKEMIA
VIRUS INFECTION 118
Introduction 118
Materials and Methods 118
Results 120
Discussion 120
X SUMMARY 129
APPENDICES
A PLAT OF THE UNIVERSITY OF FLORIDA DAIRY
RESEARCH UNIT 134
B AVERAGE MONTHLY HIGH AND LOW TEMPERATURES
AND RAINFALL BETWEEN JULY 1, 1979, AND
SEPTEMBER 30, 1981, FOR GAINESVILLE,
FLORIDA 135
vi

PAGE
C MONTHLY FREQUENCIES OF CALVES BORN ALIVE
BETWEEN JULY 1, 1979, AND JUNE 30, 1931,
AT THE UNIVERSITY OF FLORIDA DAIRY
RESEARCH UNIT 136
D LOCATION SITES AT THE DAIRY RESEARCH UNIT . . 137
E PRECIPITATION LINES OF AGAR-GEL IMMUNO¬
DIFFUSION 144
LIST OF REFERENCES 145
BIOGRAPHICAL SKETCH 166
vii

Abstract of Dissertation Presented to the Graduate Council
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy
EPIDEMIOLOGY OF NATURAL TRANSMISSION
OF BOVINE LEUKEMIA VIRUS INFECTION
by
Mark Cy Thurmond
May 1982
Chairman: Michael Burridge
Major Department: Animal Science
A 27-month study examined 473 dairy cattle for associa¬
tions between bovine leukemia virus (BLV) infection and host
and environmental factors. Cattle sera were tested at
monthly intervals for BLV antibodies by agar-gel immuno¬
diffusion using the glycoprotein-51 antigen. A model of BLV
colostral antibody decay in 130 calves predicted infection
in calves less than six months of age and estimated anti¬
body half-life to be 27.1 ±1.2 days. Colostral antibody
decay did not differ between BLV-infected and noninfected
calves for slope (p = 0.45) or intercept (p = 0.43). By 95
days of age, 50% of the calves had no detectable BLV
colostral antibodies.
Of 125 calves born to BLV-infected cows and followed
for at least four months, eight (6.4%) had precolostral BLV
antibodies, as determined by radioimmunoassay using the
glycoprotein-51 antigen. In útero infection with BLV was
viii

not associated with dam age (p = 0.86), dam parity (p = 0.83),
breed (p = 0.66), sex (p = 0.11), or stage of gestation in
which the dam was infected (p = 0.50). Calves infected in
útero did not pose an increased risk of infection to calves
penned next to them (p = 0.61).
Prevalence rates of infection were 9%, 16%, and 63% at
6, 16, and 27 months of age, respectively. Age-specific
rates of infection were not associated with dam age (p =
0.79), dam parity (p=0.75), dam BLV-status (p = 0.46), breed
(p = 0.86), or BLV-status of colostrum consumed (p=0.50).
An algorithm was described which allocated probabili¬
ties of infection to locations occupied by an animal prior
to detection of infection. Small calf pastures were associ¬
ated with less infection than was the calf barn (p< 0.05) .
No less infection was associated with individual outdoor
calf pens compared to contiguous indoor pens (p>0.05).
Risk of infection associated with the dry herd was five
times that for heifer pastures (p< 0.0001) and accounted
24 infections per 100 heifers per 100 days at risk.
Vaccination for infectious diseases was not associ¬
ated with increased BLV infection (p=0.33). Infection
rates were not associated with month of birth (p=0.24) or
with season of potential arthropod vectors (p= 0.20) .
Heifer infection was likely to occur in late winter or
spring (p = 0.01) .
ix

CHAPTER I
INTRODUCTION
Bovine leukemia virus (BLV) has been shown to be the
causative agent of enzootic bovine leukosis, a neoplastic
disease of cattle (Callahan et al., 1976; Kettmann et al.,
1976; Miller et al., 1969). Bovine leukosis is believed to
have spread to western European countries from the Baltic
region during World War I (Bendixen, 1965). Following
World War II, efforts were undertaken in some European
countries to reduce the tumor incidence rate through hemato¬
logic examinations for persistent lymphocytosis, a phenomenon
associated with bovine lymphosarcoma (Bendixen, 1965).
After discovery of BLV, and subsequent development and use
of serologic methods for mass screening (Hoff-Jorgensen et
al. , 1978 ; Miller et al., 1969; Miller and Van Der Maaten,
1976a; Onuma et al., 1975; Schmidt et al., 1978), eradica¬
tion of enzootic bovine leukosis progressed rapidly (Bause
et al., 1978; Mammerickx et al., 1978a; Straub, 1978b).
In order to preserve gains made in these programs,
restrictions were placed on BLV-seropositive cattle and on
semen entering countries either free from BLV or with BLV
control programs (Miller, 1980). Such restrictions have
placed an economic burden on the cattle export markets of
the United States (Mix, 1979). Because of the high genetic
1

2
quality of American cattle, eradication or control of BLV
infection using European methods of test and slaughter
would not be a pragmatic alternative for the American pro¬
ducer. Interest, therefore, has focused on prevention of
transmission and test and segregation within a herd (Miller
and Van Der Maaten, 1978a) .
A prerequisite to control of BLV in a herd is a clear
understanding of natural transmission of infection from
fetal life to adulthood or to the age at which heifers
would move to export markets. Several constraints make the
study of natural transmission patterns difficult and may
explain the lack of reports of long-term prospective studies
in the literature. A major obstacle is the necessity for a
large sample of animals to be tested at close intervals
over a long time period. At the same time changes in man¬
agement or environmental factors .must be recorded.
The device used to measure infection must be sensitive,
specific, inexpensive, simple, and meet specifications of
other programs. This necessitates the use of agar-gel im¬
munodiffusion because it fulfills the above conditions
(Miller, 1980). Definition of infection by a serologic
test, however, has important limitations. For instance,
discrimination has not been made between colostral anti¬
bodies and infection-induced antibodies in calves less
than six to seven months of age which consumed colostrum
from a BLV-infected cow (Ferrer et al., 1977b). Another
problem in defining infection is that seroconversion may

3
lag behind BLV infection by as much as two to three months
(Mammerickx et al., 1980; Straub, 1978b; Van Der Maaten and
Miller, 1978b, 1978c).
These constraints are not unique to the study of the
epidemiology of BLV transmission. It is important, there¬
fore, that designs for the study and eventual control of
BLV be generally applicable to the study of other diseases
and infections.
Examination of risks of BLV infection in a large cattle
population over a 27-month period is presented here as a
logical progression from the fetal environment to adult¬
hood. Detection of BLV infection based on serologic cri¬
teria is used as a proxy for infection. The intent is not
to attempt statements about specific routes of BLV infec¬
tion, but to describe temporal and spatial patterns of
natural infection observed in animals studied. Furthermore,
factors possibly associated with deviations in those pat¬
terns will be examined using existing analytic methods in
a framework applicable to other diseases. In addition, new
techniques are presented which improve the efficiency of a
serologically-based diagnosis.

CHAPTER II
LITERATURE REVIEW
Bovine Leukemia Virus Infection
Clinical Appearance
Manifestations of infection with BLV vary from no
signs to persistent lymphocytosis or to lymphosarcoma
(Abramova et al., 1974; Grimshaw et al., 1979; Kenyon and
Piper, 1977; Kumar et al., 1978; Sorenson, 1979; Stober,
1968). Clinical signs of tumor involvement usually are
seen in cattle over five years of age and are referable to
the organ system involved (Abramova et al., 1974, Grimshaw
et al. , 1979; Sorenson, 1979; Stober, 1968).
Sporadic bovine leukosis (i.e., juvenile, thymic, or
cutaneous leukosis) is not associated with BLV infection
(Bundza et al., 1980; Chander et al., 1977; Onuma, 1978;
Onuma et al., 1979; Richards et al., 1981; Straub and
Weiland, 1977).
In the absence of tumor involvement, BLV-infected
animals do not appear to suffer production losses (Langston
et al., 1978).
Distribution
Bovine leukemia virus infection is a ubiquitous infection
throughout the world (Burny et al., 1980; Burridge et al.,
4

5
1981). A survey of cattle in the state of Florida recently
estimated the infection rate of BLV in dairy cattle to be
48% (Burridge et al., 1981).
Bovine Leukemia Virus
Discovery of BLV was made following phytohemagglutinin
stimulation of lymphocytes from cattle with lymphosarcoma
(Miller et al., 1969). The virus is classifed as a single-
stranded RNA retrovirus (Burny et al., 1980). It is spheri
cal in shape with a diameter of 60-125 nm (Calafat et al.,
1974; Calafat and Ressang, 1977a, 1977b; Dutta et al.,
1970; Miller et al., 1969).
Several viral proteins have been described. There are
at least two glycoproteins, gp-30 (Dietzschold et al.,
1978) and gp-51 (Onuma et al., 1975), which constitute the
outer shell of BLV (Burny et al., 1980; Devare and
Stephenson, 1977; Driscoll et al., 1977). An ether-
resistant protein constitutes the internal or core anti¬
gen, known as p-24 (Gilden et al., 1975; McDonald and
Ferrer, 1976; Miller and Olson, 1972). The BLV genome
codes for a reverse transcriptase which has a unique re¬
quirement for Mg++ (Dietzschold et al., 1978; Gilden et
al. , 1975; Graves et al., 1977; Kettmann et al., 1976).
Six mutant strains of BLV have been investigated recently
(Couez et al., 1981; Kettmann et al., 1981).
Several investigators have identified BLV as a C-type
virus (Burny et al., 1980; Dutta et al., 1970; Ferrer et al

6
1971; Kawakami et al., 1970; Mussgay et al., 1977; Stock
and Ferrer, 1972; Van Der Maaten et al., 1974; Weiland
and Ueberschar, 1976). Others have been reluctant to de¬
scribe BLV as a B- or C-type virus since immature viruses
are rarely found outside the cell (Calafat et al., 1974;
Calafat and Ressang, 1977a, 1977b; Dekegel et al., 1977).
Comparisons of BLV with other retroviruses or onco¬
viruses by molecular hybridization have shown that BLV is
biochemically distinct from Friend mouse leukemia virus and
visna maedi virus (Kaaden et al., 1977), Rauscher leukemia
virus (Kettmann et al., 1975, 1976), simian sarcoma (wooly
monkey) virus, murine sarcoma virus, feline sarcoma virus,
and feline leukemia virus (Kettmann et al., 1975, 1977).
Other studies have demonstrated a lack of cross-reactivity
between proteins of BLV and Mason Pfizer monkey virus
(McDonald and Ferrer, 1976; McDonald et al, 1976), and
bovine syncytia virus (McDonald et al., 1976).
Pathogenesis
Tissues Involved
Replication of BLV occurs mainly in B-lymphocytes
(Kenyon and Piper, 1977; Paul et al., 1977), but an associa¬
tion with T-lymphocytes also has been reported (Takashima
et al. , 1977). Further support for B-cell involvement was
found in the expansion of the B-cell population in BLV-
infected cattle (Kenyon and Piper, 1977; Kumar et al.,
1978).

7
Following subcutaneous inoculation of leukocytes from
a BLV-infected steer, BLV was isolated from the spleen
after eight days, from leukocytes after 14 days, and oc¬
casionally from prescapular lymph nodes thereafter (Van Der
Maaten and Miller, 1978b). In that study, BLV could be
isolated from lymphocytes two to three weeks before a de¬
tectable serologic response, and virus was not isolated
from the thymus. As few as 2500 washed lymphocytes from an
infected steer have been able to transmit BLV infection to
susceptible calves (Van Der Maaten and Miller, 1978c) .
Integration of BLV in the Host Cell Genome
Results of studies using BLV-specific DNA probes sug¬
gest that BLV is an exogenous virus (Callahan et al., 1976;
Deschamps et al., 1981; Kettmann et al., 1976, 1978a, 1978b,
1979a; Kukaine et al., 1979). The DNA from lymphocytes of
BLV-infected cattle has viral sequences that cannot be
identified in the DNA from lymphocytes of noninfected cat¬
tle (Callahan et al., 1976; Kettman et al., 1976), or in
normal cell DNA from BLV-infected cows (Kettmann et al.,
1978a).
The BLV provirus is integrated in several sites of
the lymphocyte DNA in cattle with persistent lymphocytosis,
but in only one or a few sites in the DNA of cells of
lymph node tumors (Kettmann et al., 1979a, 1980a, 1980b).
Less than 5% of peripheral lymphocytes in asymptomatic,
infected cattle contain the provirus, whereas up to 33% of

8
the circulating lymphocytes in cattle with persistent
lymphocytosis contain the provirus (Kettmann et al., 1930b)
Seroconversion Period
Seroconversion following infection with BLV has been
found to occur between two and seven weeks in cattle ex¬
perimentally inoculated (Mammerickx et al., 1980; Van Der
Maaten and Miller, 1978a, 1978b). Half of the animals in
these studies had seroconverted by five weeks postinocula¬
tion. The seroconversion period was similar for sheep
experimentally inoculated by the intradermal route, oral
route, or by BLV-carrying tabanid flies (Gentile and Rutili
1978; Mammerickx et al., 1980; Ohshima et al., 1981). The
seroconversion period for animals naturally infected is
considered to be less than three months (Straub, 1978b),
and the pattern of seroconversion is believed to be similar
to that for experimentally infected animals (Van Der Maaten
and Miller, 1978b).
Transmission Via Excretions and Secretions
It is well documented that BLV can be experimentally
transmitted to cattle via blood (Mammerickx et al., 1980;
Van Der Maaten et al., 1981a) and lymphocytes (Miller and
Van Der Maaten, 1978b; Van Der Maaten and Miller, 1978a,
1978b) from infected animals. The virus has been demon¬
strated in saliva but not in prostatic fluid or feces of
infected cattle (Ressang et al.,
1980). The p-24 antigen

9
of BLV has been found 'in urine of naturally infected
animals (Gupta and Ferrer, 1980) .
Semen collected by manual massage from a BLV-infected
bull transmitted BLV infection to susceptible sheep (Lucas
et al., 1980). Another study failed to demonstrate BLV in
semen collected from BLV-infected bulls following normal
ejaculation (Miller and Van Der Maaten, 1979).
Serology
Several serologic tests for the detection of BLV have
been described for both the gp-51 and the p-24 antigen
(Burny et al., 1980). Agar-gel immunodiffusion using gp-51
has been recommended for use by member countries of the
European Economic Community (Kaaden and Stephenson, 1978),
because of its high sensitivity, simplicity, and low cost
(Miller, 1980) . Recently a radioimmunoassay procedure
was described using gp-51 (Bex et al., 1979). This test
may be the most sensitive one presently available (Miller
et al., 1981) .
Factors Examined for Associations with Bovine
Leukemia Virus Infection
Genetic Susceptibility
A genetic predisposition to enzootic bovine leukosis
and bovine lymphosarcoma was suspected before discovery of
BLV. Leukosis was observed more frequently in daughters
of affected cows than in daughters of unaffected cows

10
(Bendixen, 1965; Larson et al., 1970). Pedigree studies of
lymphosarcoma found clustering of cases by sire and/or dam
families (Crowshaw et al., 1963; Cypess et al., 1974;
Marshak et al., 1962). It also was observed that herds
which were inbred experienced higher rates of leukosis and
lymphosarcoma than did noninbred herds (Abt, 1968; Laktionov
and Nakhmanson, 1972), but purebred herds were found to
have lower rates of leukosis than nonpurebred herds
(Anderson et al., 1971).
One study estimated the heritability of susceptibility
to BLV infection to be 0.44 ±0.22 (Burridge et al., 1979).
A study of lymphosarcoma, however, was not able to associate
the disease with serologically defined antigens controlled
by the BoLA-A locus (Takashima and Olson, 1978).
Parental Infection with Bovine Leukemia Virus
The effect of BLV infection of the dam on subsequent
BLV infection in the offspring has been examined by several
investigators. In one report, dam status appeared to have
a significant influence on progeny infection (Baumgartener
et al. , 1978), but the authors felt that such an effect may
have been due to high prevalence rates in some herds. In a
longitudinal study, no association was found between dam
status and age at which progeny became infected (Olson et
al., 1978). Reports on cross-sectional studies concluded
that presence of BLV antibodies in the dam was not associ¬
ated with subsequent progeny infection (Hofirek, 1980;
Valikhov, 1973) .

11
In a large study of progeny from BLV-infected, AI bulls,
offspring from infected sires did not have as high a rate of
subsequent BLV infection as did those from noninfected sires
(Baumgartener et al., 1978).
Sex
Few studies have examined for associations between
BLV infection and sex. Reports in which sex effects were
studied suggested no difference in infection rates between
males and females (Baumgartener et al., 1975; Evermann et
al. , 1980) .
Breed
It has been reported that many different breeds are
susceptible to BLV infection (Burridge et al., 1981; Marin
et al., 1978). Analysis of data from a survey of Florida
cattle suggested that Jerseys had a higher infection rate
than Holsteins (Burridge et al., 1981). However, a study
within a Florida dairy herd indicated no difference existed
between rates of infections for Jerseys and Holsteins
(Burridge et al., 1979).
Age
Age-specific prevalence rates of BLV infection have
been shown to follow a characteristic sigmoidal curve.
Rates increased linearly from one to four years of age,
after which they plateaued (Burridge et al., 1979, 1981;

12
Chander et al. , 1978; Evermann et al., 1980; Ferrer et al. ,
1976; Hofirek, 1980; Mammerickx et al., 1978a, 1978b;
Marin et al., 1978; Olson et al., 1973; Piper et al., 1979).
Peak prevalence rates of infection were observed at four
years of age in beef cattle and at more than nine years of
age in dairy cattle (Burridge et al., 1981). Ages at which
a sharp, linear increase in rates occurred varied from study
to study and from herd to herd. In some herds rates of
infection began to level off at two to four years of age
(Burridge et al., 1979; Olson et al., 1973), while in other
herds rates reached a plateau at four to five years of age
(Chander et al., 1978; Hofirek, 1980; Mammerickx et al.,
1978a, 1978b; Marin et al., 1978).
A few studies have approached age-specific rates of
infection in a longitudinal design using birth cohorts..
Results of one of these investigations showed that animals
of similar ages experienced different rates of infection,
according to the birth cohort (Wilesmith et al., 1980).
In the other study, each new 12-month cohort entered the
herd with a lower prevalence rate than did the previous
cohort. Rates within a cohort did not appear to change as
cattle aged. It was suggested further that higher preval¬
ence rates of infection observed in older animals in
cross-sectional studies represented high-rate cohorts
(Huber et al., 1981).

13
Transmission of Bovine Leukemia Virus Infection
In Utero
Rates of natural in útero infection with BLV have been
reported to range from 3% to 25% (Ferrer et al., 1976,
1977a, 1977b; Piper et al., 1979). Stage of gestation dur¬
ing which a dam is experimentally infected has not been
associated with the frequency of infection in progeny (Van
Der Maaten et al., 1981b).
Physical Contact
Close physical contact between infected and susceptible
cattle is believed to be a prerequisite to BLV transmission
(Ferrer and Piper, 1981; Maas-Inderwiesen et al., 1978;
Miller and Van Der Maaten, 1978a; Wilesmith et al., 1980).
Newborn calves were more likely to develop leukosis when
placed in close contact with leukotic cows (Straub, 1971).
Infection rates increased during winter months in one herd
studied, suggesting transmission associated with indoor
housing conditions (Wilesmith et al., 1980). Limiting
physical contact by vacating a stall between animals or by
placing a single fence between animals appeared to retard
transmission of infection (Miller and Van Der Maaten, 1978a).
Arthropod Vectors
Bovine leukemia virus has been isolated from the mid¬
gut of horseflies after feeding on a BLV-infected cow

14
(Bech-Nielsen et al., 1978). In an experimental study,
horsefly transmission of BLV infection to sheep was demon¬
strated (Ohshima et al., 1981). It has been suggested
that high rates of infection observed in animals during
summer months support the hypothesis of vector-borne trans¬
mission of BLV infection (Bech-Nielsen et al., 1978; Onuma
et al. , 1980). Another study, however, observed higher
rates of infection during winter months (VJilesmith et al. ,
1980) .
Ixodes ricinus ticks have been suggested as a possible
explanation for geographic differences in rates of infec¬
tion in Sweden (Hugoson and Brattstrom, 1980) .
Aerosol
Intranasal instillation of BLV-infected lymphocytes
produced infection in one of two calves and an aerosol
exposure to BLV-culture fluids produced infection in two of
two calves (Van Der Maaten and Miller, 1978c). Both methods,
however, also exposed the oral cavity and the latter method
exposed the conjunctivae.
Oral
Bovine leukemia virus or BLV-like particles have been
identified in milk and colostrum of BLV-infected cows and
cows with lymphosarcoma (Dutcher et al., 1964; Jensen and
Schidlovsky, 1964; Miller and Van Der Maaten, 1979;
Schulze et al., 1966). Transmission of BLV by the oral

15
route has been demonstrated by inoculation of leukemic
blood into neonatal lambs (Mammerickx et al., 1976a), by
inoculation of lymphocyte cultures into colostrum-deprived
calves (Miller et al., 1972; Van Der Maaten and Miller,
1978c), and by feeding BLV-infected lymphocytes in colostrum
free of BLV antibodies (Van Der Maaten et al., 1981a) .
Oral transmission has not been shown in old lambs (Hoss
and Olson, 1974) or in old calves (Van £)er Maaten and
Miller, 1978c). Infection did not occur when calves were
fed BLV-infected lymphocytes in colostrum containing BLV
antibodies (Van Der Maaten et al., 1981a). Some studies
concluded that considerable emphasis should be placed on
oral transmission, especially when bloody colostrum or
milk is fed (Parfanovich et al., 1978; Seger and Morgan,
1977). Results of other studies suggest that milk or
colostrum does not constitute a major vehicle for trans¬
mission of BLV infection (Ferrer et al., 1976; Ferrer and
Piper, 1978, 1981; Piper et al., 1975, 1979). Pasteuriza¬
tion of milk or colostrum for 30 seconds at 60°C would
probably inactivate the virus (Baumgartener et al., 1976).
Venereal
One study demonstrated the venereal transmission of
BLV infection after placing BLV-infected lymphocytes in the
cervical canal of susceptible cows (Van Der Maaten and
Miller, 1978c).

16
Iatrogenic
Intradermal inoculation of BLV has been shown to be a
viable means of transmission (Van Der Maaten and Miller,
1978c) . Iatrogenic transmission of BLV following blood
sampling procedures has been suspected (Bause et al.,
1978; Maas-Inderwiesen et al., 1978; Wilesmith, 1979).
Premunization of cattle for babesiosis and other vaccina¬
tion procedures also have been incriminated in BLV trans¬
mission (Hugoson and Brattstom, 1980; Hugoson et al.,
1968; Marin et al., 1978; Stamatovic and Jonavic, 1968).
However, transmission of BLV to sheep following intradermal
Tb testing has not been demonstrated (Roberts et al., 1981).
Infection in Other Domestic Animals
The possibility for BLV infection in species other
than the bovine was first suggested when bovine leukosis
and later bovine lymphosarcoma were transmitted to sheep
(Olson et al., 1972; Wittmann and Urbaneck, 1969). Ex¬
perimental infection with BLV has been confirmed in sheep
(Bansal and Singh, 1980; Bex et al., 1979; Gentile and
Rutili, 1978; Hoss and Olson, 1974; Mammerickx et al.,
1976a, 1976b, 1980, 1981; Olson and Baumgartener, 1978;
Van Der Maaten and Miller, 1976a), in goats (Hoss and
Olson, 1974; Mammerickx et al., 1981; Olson et al., 1981),
and in pigs (Mammerickx et al., 1981). Evidence exists
for experimental BLV infection in rabbits, but not in rats

17
(Bansal and Singh, 1980), and in guinea pigs (Lussier and
Pavilanis, 1969). Serologic evidence for BLV infection in
chimpanzees has been found (Van Der Maaten and Miller,
1976b). Passage of BLV through cattle, sheep, or goats
did not reduce the infectivity of the virus for cattle,
sheep, goats, or pigs (Mammerickx et al., 1981). Sheep
have not been found to shed BLV and thus may not be a
reservoir (Mammerickx et al., 1976b; Van Der Maaten and
Miller, 1976a).
Reviews
Bovine leukosis, bovine lymphosarcoma, and bovine
leukemia virus infection have been extensively reviewed
(Bendixen, 1965; Burny et al., 1978, 1980; Ferrer, 1977,
1979, 1980a, 1980b; Ferrer et al., 1978, 1979; Hoff-
Jorgensen, 1977; House et al., 1975; Markson, 1979;
Mussgay and Kaaden, 1978; Olson, 1974; Olson et al.,
1970; Reed, 1981; Ruppanner and Paul, 1980; Tyler, 1978;
Van Der Maaten and Miller, 19 75) .

CHAPTER III
GENERAL MATERIALS AND METHODS
Population Studied
Cattle studied were those in the University of Florida
Dairy Research Unit (DRU) herd. This population was chosen
because it had been characterized previously by a BLV
prevalence rate of 75% (Burridge et al., 1979). Calves
born from July 1, 1979, through June 30, 1981, were fol¬
lowed until death, sale, parturition, or September 30, 1981,
whichever occurred first.
Location and Climate
The DRU was located in north-central Florida (latitude
82°30' west, longitude 29°40' north). It occupied about 450
hectares of reclaimed pine flatwoods 20 km. northwest of the
University of Florida at Gainesville, Florida (APPENDIX A).
The climate was characterized by hot, humid summers and
cool, dry winters (APPENDIX B).
Management Practices
The DRU was a closed herd used as a research facility.
Two 18-month-old heifers, a Jersey (M101) and a Holstein
(M121), entered the herd, however, from a commercial dairy
18

19
(Bassett's Dairy, Montecello, FL) on May 5, 1980. Both were
negative for BLV antibodies when they entered the herd. The
Jersey had BLV antibodies by April 25, 1981, and the Hol¬
stein remained serologically negative through September 26,
1981.
Approximately 200 purebred cows were milked, 1/3 of
which were Jerseys and 2/3 Holsteins. Cattle were allowed
to.graze, but it was necessary to supplement rations with
corn silage; corn, sorghum, ryegrass, or alfalfa greenchop;
and concentrates.
Cattle were bred artificially using commercially avail¬
able frozen semen. Some semen was used, however, from
young Jersey control sires raised at the DRU. Calving
season ranged from June through December (APPENDIX C).
Calves were born in small pastures (APPENDIX D, Fig. 1) and
remained with their dams for about 12 hours. They then
were placed in either contiguous, wire pens in the calf
barn (APPENDIX D, Fig. 2) or in individual outdoor pens
(APPENDIX D, Fig. 3). Once in pens, they were fasted for
12 to 24 hours, after which time they were fed either
pooled colostrum (obtained from cows one through three days
postpartum) or bulk-tank milk for the next two to three
days. Prior to weaning at about one month of age, calves
were fed bulk-tank milk once a day. Holsteins received
9 lbs. per day and Jerseys 7 lbs. per day. Calves also
were fed concentrates ad libitum from two or three days of
age.

20
Electric dehorning, ear tagging, and tattooing were
performed during the first month of life. This usually was
not done in a serial fashion from calf to calf at one ses¬
sion, but individually, one or two calves per day.
All heifers were vaccinated for brucellosis,a clostridi-
Id c
al diseases, and leptospirosis at four months of age
and for infectious bovine rhinotracheitis (IBR),^ bovine
virus diarrhea (BVD), and parainfluenza-3 (PI-3)a at 11
months of age. Brucellosis vaccination was administered
subcutaneously in the neck and other vaccinations intra¬
muscularly in the gluteal area. Cattle were vaccinated in
groups using one or two common 18 gauge 1-1/2 inch needles
and a multidose syringe. The order in which cattle were
vaccinated was not recorded.
At the time of brucellosis vaccination, calves were
e f
wormed either with thiabendazole or levamisole. The
specific type administered to each calf was not recorded.
aStrain 19, Colorado Serum Co., 4950 New York St., Denver, CO.
b
Siteguard, Clostridium chauvoei, septicum, haemolyticum,
novyii, sordellii, perfringens Type C and D. Jensen-
Salsbery, Kansas City, MO.
c
Novalep GHP, Jensen-Salsbery, Kansas City, MO.
^RESBO 3, Norden Laboratories Inc., Lincoln, NE.
eOmnizole (paste), Merck Animal Health Division, Merck
& Co., Inc., Rahway, NJ.
^Ripercol L, American Cyanamid Co., Princeton, NJ, or
Levasole, Pitman-Moore, Inc., Washington Crossing, NJ.

21
At two to three months of age, calves were moved from
indoor pens in the calf barn, or from nearby outdoor pens,
to paddocks (APPENDIXD, Fig. 4) or to small pastures (0.3
to 0.6 ha.) (APPENDIX D, Fig. 5). At about 10 months of
age, they were moved to larger pastures (2 to 3 ha.)
(APPENDIX D, Figs. 6 and 7). Cattle in each location were
of similar ages.
Heifers were bred between 13 and 16 months of age,
except during summer months when estrous behavior was less
apparent. At 40-45 days gestation, heifers were placed, for
the first time, with adult cattle in the dry herd. For
heifers under study, this began in early January, 1981.
Holstein heifers were removed from the dry herd on May 1,
1981, and placed in pastures holding only bred Holstein
heifers. Jersey heifers continued to be placed in the dry
herd and remained there until shortly before calving.
Most bull calves were sold a few days after birth, al¬
though some were retained for veal studies or semen collec¬
tion. Management of heifers was similar to that practiced
on most commercial dairies. Heifers usually were not used
in experimental studies until after freshening.
Fly control was practiced sporadically two or three
times during summer months. Lactating cows were hand-
dusted with a commercial insecticide,3 and fly bait*3 was
aMarlate 50, E. I. DuPont de Nemoud and Co., Inc.,
Wilmington, DE.
Golden Malrin, Starbar Division of Zoecon Corp., 12200
Denton Dr., Dallas, TX.

22
scattered in the calf barn a few times during peak calf
density in the fall. Pastured heifers were not treated
for flies. Most flies observed in the calf barn were
Musca domestica feeding on decaying grain and soured milk.
Pastured cattle were bothered by large numbers of Haematobia
irritans and Stomoxys calcitrans and some tabanidae. No
ticks or lice were observed during the 27-month study.
Sampling Design
Precolostral blood samples were drawn on nearly all
calves born alive between July 1, 1979, and September 30,
1980. To increase the chance of obtaining precolostral
samples, udder bags3 were placed on cows about one week
prior to calving (APPENDIX D, Fig. 1). This prevented the
calf from nursing until a blood sample could be drawn. In
order to reduce the period of colostrum deprivation, re¬
search field personnel were notified by telephone as soon
as a cow calved. This procedure was instituted in December
1979, and calves born after this time were fed 1-2 liters
of colostrum from their own dam within one hour following
birth. After feeding, the navel was washed with a solution
of 3% Lugol's iodine. Through December 1979, calves were
bled precolostrally, at one week of age, and then at three-
month intervals. After December 1979, calves were bled
precolostrally, at two to three days of age, and then at
aNumbers C4591N-C4593N, Nasco, Fort Atkinson, WI.

23
monthly intervals beginning some time during the first month
of age. Calves born between September 30 , 1980, and June 30,
1981, were not bled precolostrally, but were bled at monthly
intervals beginning sometime during the first month of age.
Calves born after June 30, 1981, were not included in the
study. Cows were bled at two, five, and eight months of
gestation, at parturition, and at one month postpartum.
All blood samples were collected from either the jugular or
intercoccygeal vein using a sterile 20 gauge 1-1/2 inch
ci b
needle and Vacutainer tube.
Demographic Information
The following information was obtained for each calf:
BLV status of dam, age of dam, parity of dam, breed, sex,
birth date, sale date, death date, or freshening date.
Locations and inclusive dates of occupation in pens and
pastures were recorded for all cattle as long as they were
followed. As soon as heifers began entering the dry herd,
all cattle in that group were sampled monthly to determine
the BLV status of animals exposed to heifers being studied.
No interventions were made in routine management of calves
or heifers except for colostrum feeding, navel washing, and
monthly mustering and bleeding.
No.
5746,
Becton-Dickinson
and
Co. ,
Rutherford,
NJ.
'No.
6512,
Becton-Dickinson
and
Co. ,
Rutherford,
NJ.

24
Serum samples were tested for presence of antibodies
to BLV glycoprotein-51 antigen (gp-51)a using agar-gel im¬
munodiffusion (AGID), as previously described (Burridge
et al., 1979). Gel plates were incubated at 24-27 C in an
humidified chamber for 48 hours before being read with the
b . ...
aid of a direct light beam. Formation of precipitation
lines of identity with positive control sera indicated
presence of BLV antibodies (APPENDIX E). Serial two-fold
dilutions using phosphate buffered saline were made of
all positive sera and then these dilutions were retested to
determine end-point titers.
All precolostral sera from calves lost to follow-up
before four months of age and negative on AGID were re¬
tested using a radioimmunoassay (RIA) procedure with gp-51
(Bex et al., 1979). Samples precipitating more than 15%
of labeled antigen were considered positive for BLV anti¬
bodies. Persistence of antibodies or an increase in BLV
antibody titer was considered evidence of BLV infection.
Precolostral sera from calves with evidence of BLV infec¬
tion at some later date were retested by RIA.
aAntigen supplied in the Leukassay-B kit, Pitman-Moore,
Inc., Washington Crossing, NJ, and by Dr. J. Miller, USDA,
Ames, IA.
^Model 651, American Optical Corp., Buffalo, NY.
cDulbecco's formula, Flow Laboratories, Inc., McLean, VA.
Performed by Dr. M. J. Schmerr, USDA, Ames, IA.

25
Other Species Examined
The DRU maintained between six and eight sheep and
goats during the 27-month study. These animals were kept
in a small pasture, separated from any cattle under study
by at least two fences. Tests for presence of antibodies
to BLV were negative for all sheep and goats in the fall of
1980 and 1981.
Several cats also inhabited the DRU during the study
period. Three of the tamer cats were bled in October 1981,
and no detectable BLV antibodies were found.
Diseases or Conditions Observed
During the 27-month study, lymphosarcoma was diagnosed
in two cows following postmortem examination. Both were
Jerseys, one six years old and the other five years old.
Although no health records were kept, nearly all neo¬
natal calves experienced at least one episode of diarrhea
and bronchopneumonia, and several died. According to clini¬
cal and pathological reports, a common cause of death,
particularly prior to December 1979, was septicemia result¬
ing from omphalophlebitis and/or hypogammaglobulinemia.
Chronic dysentery was prevalent among calves two to six
months of age. This was probably due, at least in part, to
coccidia and trichostrongyles, as suggested by oocysts and
eggs found on fecal flotation. Many calves in this age
group, particularly bull calves in nutrition trials, were

26
quite cachectic. Heifers older than six months appeared
less affected.
Data Collection and Computer Programs
Data were transcribed onto computer sheets from which
IBM cards were punched. Files were maintained on tape at
the Northeast Regional Data Center (NERDC), University of
Florida, Gainesville, Florida. Computer systems available
through NERDC for statistical analysis were the Statistical
Analysis System (SAS) version 79.5,a Biomedical Computer
Programs (BMDP), and the McGill University System for
Interacting Computing (MUSIC) version 4.1, 1978.
aSAS User's Guide, SAS Institute Inc., Raleigh, NC.
^BMDP, P-series, University of California Press, Berkeley,
1979.

CHAPTER IV
IN UTERO TRANSMISSION OF BOVINE LEUKEMIA VIRUS
Introduction
Since BLV is currently considered an exogenous virus
(Callahan et al., 1976; Kettmann et al., 1976, 1978a,
1978b, 1979a, 1979b; Kukaine et al., 1979) and there is
no evidence for natural transmission of BLV via semen
(Baumgartener et al., 1978; Miller and Van Der Maaten,
1979; Ressang et al., 1980), prenatal infection is most
likely a consequence of in útero transmission. Suggested
rates for in útero transmission of BLV infection have ranged
from 3% to 25% (Ferrer et al. , 1976, 1977a, 1977b; Piper
et al., 1979). Highest rates were observed, however, in
an inbred herd in which selection for bovine leukemia had
been practiced (Piper et al. , 1979) . The BLV status of the
dams was not stated in some reports (Ferrer et al., 1976,
1977a, 1977b); therefore, rates could have been higher
had they been stated correctly in terms of calves born to
infected cows.
It is not known what factors, if any, predispose a
fetus to infection with BLV. Stage of gestation in which
the dam was infected has not been associted with fetal
infection (Van Der Maaten et al., 1981b). If predisposing
27

28
factors are present, calves and/or dams with the related
characteristic could be segregated, thus reducing post¬
natal transmission. Otherwise, efforts could be focused on
other aspects of transmission control.
The purpose of this chapter is to describe observed
rates of natural precolostral antibodies to BLV in a large
sample of random-bred calves and to examine for associa¬
tions between those rates and certain characteristics of
the calves and their dams.
Materials and Methods
Data Analyzed
Calves examined were those born to BLV-infected dams
and bled precolostrally. A BLV-infected dam was defined as
one which had BLV antibodies up to one month postpartum.
Calves were divided into two groups: (1) those post-
colostrally positive for BLV antibodies and followed for
four months or more, or postcolostrally negative for BLV
antibodies and followed for one month or more, and (2) those
with postcolostral BLV antibodies and not followed for four
months. A positive precolostral sample was considered
invalid, if, after following the calf for four months or
more, there was no evidence for BLV infection. Evidence
for BLV infection was based on a rising antibody titer
during the first six months of age, on observation of titers
outside the 95% prediction level of decay of BLV colostral

29
antibodies (CHAPTER V), or on persistence of BLV anti¬
bodies beyond six months of age.
Analysis
Rates of precolostral antibodies in both groups of
calves were examined for associations with breed and sex of
calf. Analyses were performed using the FUNCAT program, a
procedure for analysis of categorical data (Grizzle et al.,
1969) offered by SAS. The model was presence (or absence)
of precolostral BLV antibodies = breed + sex + breed x sex.
The response function was the difference between the pro¬
portion of calves with and the proportion without pre¬
colostral antibodies to BLV, or, as indicated by SAS, 1 -1.
Differences in age and parity distributions for dams
of calves with precolostral antibodies and dams of calves
without precolostral antibodies were examined using the
NPARlWAY program of SAS, a two-sample Wilcoxon Rank Sums
test for nonnormal distributions. Fisher's exact test,
from the STATPAK subsystem of MUSIC, was used to calculate
the probability of association between the stage of gesta¬
tion of seroconversion to BLV by the dam and occurrence of
precolostral antibodies in calves followed four months or
more.
Results
Of 346 calves born during the period July 1, 1979,
through September 30, 1980, 280 calves were bled

30
precolostrally and, of those, 223 were from BLV-infected
dams. Because many calves were sold or were not followed
for more than a few months, only 125 calves were born from
BLV-positive cows, bled precolostrally, and followed for
four months or more (Table IV-1). Eight (6.4%) of these
calves had precolostral antibodies and antibodies persist¬
ing beyond six months of age (Table IV-1, IV-2). In the
group of 223 calves, 18 (8.1%) had detectable precolostral
antibodies (Table IV-1).
Precolostral antibodies were detected with similar
frequency in Jersey and Holstein calves, both in the fol¬
lowed group (p = 0.66) and for all calves (p = 0.80) (Table
IV-3). When all calves were examined, males showed a
significantly higher rate of precolostral antibodies than
did heifers (p = 0.04). There was no such association in
the 125 calves followed (p = 0.11) (Table IV-3). No sig¬
nificant interactions between breed and sex were detected
for either the group followed (p=0.91) or for all calves
(p = 0.64) (Table IV-3) .
No statistical differences were detected between dis¬
tributions of age (p = 0.86) or parity (p = 0.83) for dams
having calves with precolostral antibodies and for dams
having calves without detectable precolostral antibodies
(Table IV-4). Complete serologic records were available
for 76 cows seroconverting before the second month of ges¬
tation and for 14 cows seroconverting after the second
month. Those seroconverting after the first trimester of

31
gestation showed no more tendency to have a calf with pre-
colostral antibodies to BLV than did cows seroconverting
before the first trimester (exact p = 0.50) (Table IV-5) .
Discussion
The ruminant fetus may be particularly susceptible to
infection because (1) syndesmochorial placentation does not
allow transfer of maternal antibodies to the fetus; (2) the
fetal immune system is not fully functional; and (3) micro¬
bial activity can take place in fetal cells (Osburn, 1981).
Since placentation restricts passage of antibodies to the
fetus, presence of fetal immunoglobulins is indicative of
infection by, or exposure to, an antigen or of placental
leakage of globulins (Brambell, 1970; Husband et al., 1972).
Although no estimates are available for frequency of
placental leaks, such events are believed to be rare
(Brambell, 1970). This has been confirmed by several
studies of in útero infection based on fetal infection and
fetal or precolostral serology (Braun et al., 1973; Dunne
et al., 1973; Fennestad and Borg-Petersen, 1962; Gibson
and Zemjanis, 1973; Horner et al., 1973; Kniazeff et al.,
1967; Osburn and Hoskins, 1971; Osburn et al., 1974;
Van Der Maaten et al., 1981b) .
The main difficulty when studying in útero infection
as it occurs naturally in a population, using serologic
detection, is one of logistics. Efforts should be made to
sample the calf as soon after birth as possible and before

32
it nurses. For this reason, cows were fitted with udder
bags a week or two before their due-date. However, prior
to December 1979, research personnel were lax about udder
bag procedures and precolostral sampling. As a result,
some calves could have sucked BLV-positive cows without
udder bags. Precolostral samples could be partially veri¬
fied, however, by following calves to determine if they
became serologically negative. For purposes of analysis,
two groups of calves were described based on confidence in
precolostral samples. A follow-up time of four months was
selected because 80% of calves consuming colostrum contain¬
ing BLV antibodies were negative by 120 days of age (CHAPTER
V), and prediction of infected calves, therefore, could be
made with confidence.
Radioimmunoassay using gp-51 antigen has been shown
to be a highly sensitive test of BLV antibodies and may
detect infected animals up to 10 days sooner than AGID
(Miller et al., 1981). After screening with AGID, negative
sera were retested by RIA to identify calves infected in
late gestation. Additional calves identified as precolos-
trally seropositive by RIA may have consumed colostrum, as
previously mentioned. More confidence, therefore, should
be placed on the precolostral antibody rate of 6.4% than on
that of 8.1% because of these logistical problems.
Since reported in útero infection rates of 10% or
more may have counted calves born to negative dams, those
figures represent minimal rates for calves born to infected

33
dams. In addition, syncytium induction assay, virus neu¬
tralization, and/or immunofluorescence assay were used in
those studies to detect BLV or BLV antibodies. These tests
may be less sensitive than RIA with gp-51 for detection of
BLV infection (Miller et al., 1981; Van Der Maaten and
Miller, 1977), and, therefore, in útero infection may have
been underestimated further.
The most likely explanation for the discrepancy between
rates observed in this study and those reported in other
studies rests in innate features of the populations ex¬
amined. Higher rates (e.g., 14%, 18%, and 25%) were ob¬
served in a Jersey herd in which animals had been inbred
and selected for leukemia (Piper et al., 1979). Such high
rates may suggest a weakening of placental integrity due to
inbreeding allowing for passage of maternal blood into the
fetus. In any case, it is unlikely that the higher rates
are representative of in útero infection in a typical dairy
herd.
A rate of 3% was observed in 37 calves from a multiple-
case herd (Ferrer et al., 1976). Again the BLV status of
dams was not reported, and, therefore, rates in calves from
infected cows were possibly higher. Furthermore, caution
should be taken in considering a rate based on only one in¬
fected calf from a small sample of 37 calves.
Results of this study indicated that the risk of BLV
transmission did not differ between older, multiparous cows
and younger or primiparous cows. This suggests that

34
transmission is not a consequence of loss of placental
integrity associated with increasing physiologic age or
pregnancies. In addition, stage of gestation at maternal
infection did not appear to influence fetal infection rates,
in accordance with observations from experimental studies
(Van Der Maaten et al., 1981b).
Reports on studies of breed effects on BLV infection
rates indicate that many breeds are susceptible (Burridge
et al., 1981; Marin et al., 1978). One report concluded
that higher infection rates occurred in Jerseys (Burridge
et al., 1981), but these differences could have been at¬
tributable to high rates in particular age cohorts (Huber
et al., 1981; Wilesmith et al., 1980). Furthermore, no
breed effects were found in a previous study at the DRU
(Burridge et al., 1979).
Although fetal sex showed some statistical association
with precolostral antibodies when both groups were combined,
this possibly resulted from less fastidious postnatal
sampling of bull calves. Colostrum may have been consumed
by more bulls than heifers prior to sampling because less
attention is usually paid to postnatal care of bulls.
From a practical standpoint, knowledge of dam age or
parity probably would not assist in control or prediction
of in útero BLV infection. Economic justification for
efforts to control in útero infection seems unlikely with
a rate as low as 6.4%.
Even though control may not be

35
possible, awareness of in útero infection is essential
in planning postnatal management of BLV transmission.

Table IV-1. Summary of results of precolostral sampling for antibodies to bovine
leukemia virus (BLV) between July 1, 1979, and September 30, 1980; at
the University of Florida Dairy Research Unit, Hague, Florida.
Holstein
Jersey
Number of calves
Females
Males
Females
Males
Total
Born
136
112
47
51
346
Bled precolostrally
102
97
42
39
280
Born to BLV-infected dam
74
79
36
34
223
Followed for four months or more
67
13
35
10
125
Precolostral BLV antibodies (%)*
2(3.0)
2(15.4)
2(5.7
2(20)
8(6.4)
Not followed for four months
7
66
1
24
98
f
Precolostral BLV antibodies (%)'
0
8(12.1)
0
2(8.3)
10(10.2)
Total precolostral BLV antibodies (%)
^ 2(2.7)
10(12.7)
2(5.6)
4(11.8)
18(8.1)
ic
Percentage based on number of animals followed for four months or more.
^Percentage based on number of calves followed less than four months,
t
Percentage based on all animals bled precolostrally and born from BLV-positive dams.

Table IV-2. Calves followed for six months or more which had pre-
colostral and persisting antibodies to bovine leukemia
virus (BLV).
Calf number
Dam parity
Dam age
(months)
Breed
Sex
H375*
2
37
Holstein
F
H955*
3
59
Holstein
F
H1002B*
1
24
Holstein
M
H1038B*
2
37
Holstein
M
J166*
3
56
Jersey
F
Jl7lt
2
35
Jersey
F
J194B^
1
23
Jersey
M
J200B*
5
73
Jersey
M
•k
Presence of antibodies determined by agar-gel immunodiffusion
using glycoprotein antigen.
t
Antibodies were detectable only by radioimmunoassay using
glycoprotein antigen.

Table IV-3. Associations of sex
antibodies to bovine
and breed
leukemia
of calf with
virus (BLV).
presence of
precolostral
Group
n
df
Chi Square
Probability
Calves followed four months
or more
125
Intercept
1
86.87*
0.0001
Sex
1
2.54
0.1107
Breed
1
0.19
0.6606
Sex by breed
1
0.01
0.9102
All calves
223
Intercept
1
446.83
0.0001
Sex
1
4.17
0.0411
Breed
1
0.06
0.8045
Sex by breed
1
0.22
0.6360
*
Analyses performed using the FUNCAT procedure for categorical data analysis, SAS
User's Guide, 1979.

Table IV-4. Results of Wilcoxon Rank Sums test for association of dam age and parity
with presence of precolostral antibodies to bovine leukemia virus (BLV)
in offspring.
Precolostral
BLV antibodies*
Number of+
offspring-
*
Dam age
(months)
Dam parity
Sum of
ranks^
Expected
under HO
Mean
rank
p>|z|
Sum of
ranks
Expected
under HO
Mean
rank p>> | z |
Present
8
482
504
60.25
486
504
60.75
.8283
.8599
Absent
117
7393
7371
63.19
7389
7371
63.15
*
All dams were positive for BLV antibodies.
Determined by agar-gel immunodiffusion and radioimmunoassay using glycoprotein antigen.
Only offspring followed for four months or more were included in the analysis.
§ .
Midranks were used for ties.

Table IV-5. Frequency of precolostral antibodies to bovine leukemia virus (BLV) in
calves born to cows with antibodies to BLV prior to the second month
of gestation and in calves born to cows seroconverting sometime be¬
tween the second month of gestation and parturition.
Antibodies to
precolostral
BLV in
*
serum
Stage
Number of calves
of gestation in which the dam seroconverted
Before
second
month
After second
month
Total
Present
4 +
0
4
Absent
72
14
86
Total
76
14
90
*
Presence of
antibodies
determined by
agar-gel
immunodiffusion and
radioimmunoassay.
+Fisher's exact probability = 0.502.
o

CHAPTER V
DECAY OF COLOSTRAL ANTIBODIES TO
BOVINE LEUKEMIA VIRUS
Introduction
Before postnatal transmission of BLV can be studied,
criteria for serologic detection of BLV infection must be
established. This is straightforward for an animal which
seroconverts after a period of seronegativity. However,
during the period when colostral antibodies are detectable,
it is difficult to discriminate between infected and non-
infected calves strictly by the presence or absence of anti¬
bodies. In order to more accurately define time or place of
infection, it would be helpful to detect infected calves
during the period that colostral antibodies are detectable.
This chapter will describe the decay of colostral BLV
antibodies in noninfected and infected calves and estimate
normal limits of decay in noninfected calves. It is shown
how these normal limits can be used to detect BLV-infected
calves during the first six months of life.
Materials and Methods
Data Analyzed
Titers were analyzed from calves which had colostral
antibodies on at least three observations, followed by no
41

42
serologic reaction for at least two months after the last
colostral antibody titer. These calves were assumed not to
be infected with BLV during the period when colostral anti¬
bodies were detectable because, had the virus been present,
an active antibody response probably would have been ob¬
served within two months after the last detectable colostral
titer (Mammerickx et al., 1980; Van Der Maaten and Miller,
1978b, 1978c). Furthermore, apparently to date, there is
no evidence that the presence of BLV appreciably alters the
rate of decay of colostral antibodies.
Titers also were analyzed from 14 calves which either
had precolostral antibodies that persisted throughout the
study or had antibodies persisting through eight months of
follow-up. These calves were assumed to have been infected
during at least part of the colostral-antibody period.
Only calves with titers which remained the same or declined
from previous levels were included in regression analysis.
All titers from infected calves were included in estimates
of ages at which BLV infection could first be serologically
detected.
Analysis
Titers were analyzed using an estimated weighted re¬
gression procedure (Swamy, 1971) . All computations were
performed using SAS. A linear regression predicting the
log^Q of the inverse of BLV antibody titer at various ages
was determined by pooling intercepts and slopes from

43
individual calf least squares regressions. Each vector of
regression coefficients was weighted by the inverse of its
estimated covariance matrix. The mathematical model was
Y = a + bX + u
where Y (dependent variable) was log^g °f the inverse of
the end-point titer, a was the pooled Y intercept, b was
the pooled rate of decay of log^g inverse titer, X (inde¬
pendent variable) was age in days when the titer was ob¬
served, and u was random error. Prediction bands (normal
limits) were calculated for the 90%, 95%, and 99% confidence
levels. A zero titer level was set at log^g (0.5) = -0.3.
Half-life of antibodies was estimated by
logado t - a.
2
b.
i
n
where a^ and b^ were the Y intercept and slope of the es-
th
timated regression line for the i calf and n = 130 calves.
A randomly selected set of 61 calves was used to ob¬
tain preliminary estimates of a and b and normal limits.
The validity of these estimated normal limits of BLV anti¬
body decay was tested using the remaining 69 calves as a
validation group. Since approximately 91%, 94%, and 98% of
the observations in the validation group fell within the
90%, 95%, and 99% normal limits established by the first
n
Z
i=l

44
set of calves, the two sets were combined and a final pre¬
diction model was derived based on all 130 calves.
Regression analysis was repeated for 14 infected
calves which had declining titers for at least three ob¬
servations beginning at two days of age. Tests of hypothe¬
ses of equal intercepts and slopes of colostral decay were
made using large approximate t statistics (Swamy, 1971,
p. 129).
Results
For the 130 noninfected calves, the number of positive
antibody titers per calf ranged from three to eight. One
of these calves had an early titer as high as 1:256. Dura¬
tion of colostral-BLV antibody titers ranged from 51 to 187
days with 50% of the calves serologically negative by 95
days of age (Fig. V-l).
The regression equation for all 130 calves was Y = 1.29
- 0.012X. The mean half-life of BLV antibodies was esti¬
mated to be 27.1 days ± 1.2 days. The prediction line
crossed the zero titer level at 136 days of age, while the
90%, 95%, and 99% upper prediction bands crossed at 168,
178, and 200 days of age, respectively (Fig. V-2).
Serologic diagnosis of BLV-infected calves was made
between 2 and 180 days of age using the 90% limit and be¬
tween 8 and 206 days of age using the 99% limit (Table V-l).
The regression line of BLV colostral antibody decay
for 14 infected calves was Y = 1.43 - 0.012X (Fig. V-3).

45
No differences were found between noninfected calves and
infected calves for slopes (p = 0.45) or intercepts (p = 0.43).
Discussion
Examination of individual calf regressions revealed
little deviation from linearity when titers were expressed
on the log1Q scale. The decision to set the level of a
negative titer at log^Q(0.5) was based on the two-fold
dilution scheme. Extrapolation below a titer of 1:1 can be
made with confidence because there is no reason to suspect
appreciable deviation from exponential decay below the
level detectable by AGID.
Some assumptions for estimated weighted regression
analysis (Swamy, 1971) could not be perfectly met in this
application. The distribution of log.^ °f inverse titers,
for example, cannot be assumed to be normal, particularly
as calves age, because titer values truncate at zero. Also,
the method of titer measurement results in a discrete de¬
pendent variable which would not have an exact normal dis¬
tribution. It is likely that with a sample of 130 calves
violations of these assumptions are not critical. Never¬
theless, 69 calves were assigned randomly to a validation
set to test validity of the 90%, 95%, and 99% normal limits.
Since results showed little deviation from expectations, it
can be assumed that these limits were valid. Estimated
weighted least squares analysis was performed instead of
ordinary least squares regression because the assumption of

46
independence of deviations from overall regression does not
hold when repeated measures are made on each animal (Swamy,
1971) .
It is well known that IgG is the major immune globulin
acquired from colostrum by the neonatal calf (Pierce and
Feinstein, 1965; Porter, 1972). These colostrum-derived
immunoglobulins originate from the maternal circulation
where they transfer to colostrum several weeks prior to
parturition (Brandon et al., 1971; Logan et al., 1973;
Smith, 1971; Sullivan et al., 1969). Since AGID using BLV
gp-51 antigen measures IgG^ exclusively (Matthaeus et al.,
1978), decay of colostral BLV antibodies is essentially the
decay of IgG^• The half-life of IgG^ in the bovine may vary
from 18 to 22.7 days (Brar et al., 1978; Dixon et al., 1952;
Logan et al., 1973; MacDougal and Mulligan, 1969; Smith,
1971). The longer half-life of 27.1 ± 1.2 days found in
this study may have several explanations. Use of larger
and older animals in at least one study may account for a
shorter half-life, since younger and smaller animals may
metabolize IgG^ at a slower rate (Dixon et al., 1952).
Furthermore, the rate of decay of IgG^ may be dependent on
the incidence of diarrhea in calves studied (MacDougal and
Mulligan, 1969).
The 187-day duration of colostral antibody titers to
BLV found in this study was similar to that for infectious
bovine rhinotracheitis (Brar et al., 1978) and bovine viral
diarrhea (Brar et al., 1978; Kahrs et al. , 1966; Kendrick

47
and Franti, 1974) . In another study of 21 calves, colostral
antibodies to BLV were detected for only 154 days (Fischer
and Keyserlingk-Eberius (1980). Since AGID has not been
standardized, a discrepancy of this magnitude is not sur¬
prising. A lower rate of diarrhea or consumption of a
higher quality or quantity of colostrum also could explain
the longer duration of antibodies found in our study.
The age at which infected calves could be detected was
variable within a given level of normal limits. This is not
unexpected because the critical level at which viral repli¬
cation is initiated also is variable and dependent on both
neutralizing antibody and virus concentration (Driscoll
et al. , 1977; Straub, 1978b). At the 90% prediction level,
infected calves were identified as early as 2 days and as
late as 180 days of age. At the 99% level, calves were
identified later, from 8 to 206 days of age, but fewer non-
inf ected calves were misidentified. The sensitivity of
this method varies inversely, whereas specificity varies
directly, with the level of precision (prediction).
Serologic detection of BLV-infected calves during the
period of colostral antibody decay could be used in eradi¬
cation or control programs where it would be feasible to
serially dilute serum from calves less than six months of
age. Because typical levels of passive antibodies vary
from region to region and herd to herd (Naylor, 1979), a
decay curve might be defined for noninfected calves which
is characteristic of a herd or region. Since at least three

48
positive observations are required per animal to estimate
error variance, calves could be bled at weekly intervals
for the first month and at monthly intervals thereafter.
This technique of defining upper limits of colostral
antibodies also could be used in planning strategies for
herd immunization (Kahrs et al., 1966; Kendrick and Franti,
1974). Calves would be vaccinated at the earliest age that
passive antibodies would not interfere with immunization.
Other factors, such as herd disease prevalence, antigen dose
and type, and general health conditions, also should be
considered (Brar et al., 1978; Kahrs et al., 1966; Kendrick
and Franti, 1974; Uhr and Bauman, 1961).
Colostral antibodies decayed at the same rate from the
same level in infected calves as in noninfected calves.
This validated the assumption that presence of BLV did not
alter BLV colostral antibody decay. Use of calves with no
evidence of BLV infection for at least two months beyond
the last colostral titer, therefore, should provide valid
estimates of BLV colostral antibody decay.

49
Table V-l. Ages at which bovine leukemia virus (BLV) anti¬
body titers from BLV-infected calves were above
normal limits of colostral titers of noninfected
calves.
Infected
calf number
Age (days) at
above
which logpo 1/titer*
the normal limits of
was first
90%
95%
99%
J166Í
2
2
178
J171*
153
153
153
J133*
151
151
151
J194B*
169
169
169
J200B^
38
73
206
H875^
180
180
180
coo -
00
00
00
154
154
154
11913*
155
155
155
H938§
112
112
167
H949§
2
2
8
H95st
160
160
160
H972§
137
137
163
H973§
67
67
102
H1002B^
31
31
31
H1038B^
27
27
144
H1079B§
167
167
167
MEAN
106.56
108.75
143.
00
SEM
16.54
16.07
13.
22
"ft
Antibodies measured by agar-gel immunodiffusion using
glycoprotein antigen.
"^Calves with precolostral antibodies to BLV.
*Calves with no detectable precolostral antibodies to BLV.
^Calves which were not sampled precolostrally.

50
Fig. V-l. Percentage of 130 calves with colostral anti¬
bodies to bovine leukemia virus (BLV) as a
function of age.

BLV ANTIBODY LEVEL
(LOG INVERSE TITER)
51
Fig. V-2. Prediction line of the decay of colostral anti¬
bodies to bovine leukemia virus (BLV) in 130
calves with no evidence of infection with BLV.
Upper normal limits of the prediction line are
indicated for the 90%, 95%, and 99% confidence
levels; o = values of log-j_Q 1/titer falling
above the 90% normal limit from calves not in¬
fected with BLV; a = values of log^o 1/titer from
calves infected with BLV in útero or sometime
prior to six months of age"!

BLV ANTIBODY LEVEL
(LOG INVERSE TITER)
52
Prediction line of the decay of colostral anti¬
bodies to bovine leukemia virus (BLV) in 14
calves infected with BLV in útero or sometime
prior to six months of age;
1/titer.
=values of log
10
Fig. V-3.

CHAPTER VI
AGE-SPECIFIC RATES OF DETECTION OF
BOVINE LEUKEMIA VIRUS INFECTION
Introduction
Several factors have been examined individually for
association with prevalence rates of BLV infection in previ¬
ous studies. Rates have been reported to be unrelated to
BLV-status of the dam (Hofirek, 1980; Olson et al., 1978;
Valikhov, 1978), consumption of colostrum from BLV-infected
cows (Ferrer et al., 1976; Ferrer and Piper, 1978; Piper
et al., 1975, 1979), or breed (Burridge et al., 1979).
Other studies have suggested that an association exists
between prevalence rates of BLV infection and breed
(Burridge et al., 1981), BLV status of the dam (Baumgartener
et al., 1978), type of colostrum consumed (Seger and Morgan,
1977), and age (Burridge et al., 1979, 1981; Chander et al.,
1978; Evermann et al., 1980; Ferrer et al., 1976; Hofirek,
1980; Huber et al., 1981; Mammerickx et al., 1978a, 1978b;
Marin et al., 1978; Olson et al., 1973; Parfanovich et al.,
1978; Piper et al., 1979). Because age is associated with
BLV prevalence rates, it is important to examine for the
age-specific effects of factors on rates of infection.
The objective of this chapter is to describe age-
specific rates of detection of BLV infection and to test
53

54
for differences between rates for cattle identified by
various maternal and management features.
Materials and Methods
Cattle Studied and Criteria for Detection
of BLV Infection
Cattle studied were those described in CHAPTER III.
Calves known to be infected in útero (CHAPTER IV) were ex¬
cluded from examination of postnatal infection. Detection
of BLV infection was made when BLV-gp antibodies first ap¬
peared following a period of seronegativity. In calves
showing evidence of colostral BLV antibodies, e.g., a declin¬
ing titer during the first six months of life, the time at
detection of BLV infection was determined from the model of
colostral antibody decay (CHAPTER V). A calf was detected
as infected when titers first began to increase or when a
titer fell outside the 95% normal limits of colostral anti¬
body decay, whichever occurred first. Because the precise
moment of infection could not be measured, the date of de¬
tection was used to approximate this time, assuming a uni¬
form lag period from infection to detection in all cattle.
A BLV-infected dam was defined as one which had anti¬
bodies to BLV during gestation or within one month follow¬
ing parturition. A calf was judged to have consumed colostrum
from a BLV-infected cow if the calf had detectable anti¬
bodies to BLV in the first postcolostral sample and was

55
precolostrally negative or if it had postcolostral antibody
titers that declined with age.
Analysis
Data were analyzed using survival regression tech¬
niques (Cox, 1972; Taulbee, 1979) available in the PHGLM
program of SAS. Life-table calculations and graphics were
performed using the statistical program P1L of BMDP. Fail¬
ure time was defined as the age in days when an animal was
detected as infected with BLV. Censored time was the age
when an animal died, left the herd, calved, or when follow¬
up was terminated on September 30, 1981, whichever occurred
first.
The number of cattle at risk of being detected as in¬
fected in an age interval t^, defined for graphical purposes
as 30 days, was
c .
where n^ was the number of animals entering the interval and
c^ the number censored in the interval. Conditional prob¬
ability of detection in an interval (given that detection
did not occur in the previous interval) was
where d. was the number detected as infected in the interval.
i
It was assumed that risk of detection remained constant
during an interval. The conditional probability of an

56
4- V»
animal not being detected (surviving) in the 1 interval
was
pi
= 1
The cumulative proportion remaining undetected (also known
as cumulative survival or survival rate) to the beginning
_ . th .
of the i interval was
where P^ = 1. Hazard rates (also called failure rates or
force of morbidity) were estimated at interval midpoints
and were defined as the quantity
A. = 2q./h.(1+p.) ,
i ± i
t h
where h. was the width of the i interval. This rate was
i
a linear interpolation estimate based on a life table rep¬
resentation of a survival curve.
Standard errors of cumulative survival functions and
hazard rates were calculated as described in the PlL pro¬
gram of BMDP for all animals born between July 1979 and
June 30, 1981.
Relationships between hazard rates and other variables
were assessed using the model of the hazard at time t, as
previously described (Cox, 1972) because it adjusts for
censoring in the data. This model is
X(t,zi) = exp(z^8)X(t) ,

57
where g is a vector of unknown parameters and z is the vari¬
able under study. The variable z can take on indicator
values (e.g., 1=positive dam and 0=negative dam) or
continuous values as in dam age. Implicit in this model
is the assumption that hazard rates for individuals with
different values of the covariate are in constant ratio
over time, regardless of the underlying hazard rate
(Taulbee, 1979). An obvious violation of the proportional
hazards assumption occurs when survival curves cross. This
often is the case with actual data, and it is possible to
examine changes in hazard rates with age using an alterna¬
tive function described by Taulbee in which a new variable,
zt, is defined. This allows the ratio of hazard functions
to differ and permits examination for age-by-factor inter¬
actions. Conclusions based on this test, however, must be
extremely tentative, since the differences detected as
significant are unknown.
Correlation coefficients were calculated using the
CORR program of SAS to describe relationships between the
various factors investigated. To examine effects of factor
interactions on survival, correlation coefficients were
computed from the variance-covariance matrix of parameter
estimates when all factors were included in the survival
model. High negative correlations between regression pa¬
rameters for two factors were interpreted as a reduction in
the effectiveness of one factor in explaining survival when
the role of the other factor on survival became more

58
important. High positive correlations identified factors
which were jointly effective in explaining survival.
Factors examined were dam age (months), dam parity
(0=primiparous, 1=multiparous), dam BLV status when the
animal under study was born (1=positive, 0=negative),
type of colostrum consumed (1 = from a BLV-infected cow,
0 = not from a BLV-infected cow), and breed (l = Hostein,
0 = Jersey) .
Results
A total of 473 live calves entered the survival analy¬
sis at birth. Of these, nine were detected as infected in
útero (CHAPTER IV) and 54 infected postnatally. Two ani¬
mals were followed through 780 days of age (Table VI-1).
Estimates of prevalence rates of infection increased from
2.3% at birth to 63% at 27 months of age (Fig. VI-1).
Survival rates (Fig. VI-1), hazard rates (Fig. VI-2), and
proportion of animals detected as infected for various age
groups (Fig. VI-3) demonstrated four possible age-related
stages of detection. The first stage, prenatal infection,
has been characterized previously (CHAPTER IV). A second
stage appeared as increased hazard rates during the first
six months of life. This was followed by a 10-month period
of sporadic detection. The fourth stage, beginning at 16
months of age, was characterized by sharply increasing
hazard rates of detection through 27 months of age.

59
Results of statistical analyses using Cox's procedure
are presented in Table VI-2. No differences were found in
hazard rates when variables were examined separately without
the age covariate. However, significant age interactions
were suggested for all factors studied after inclusion of zt
and use of the test by Taulbee (Table VI-2). Graphically,
factor-by-age interactions were indicated for calves con¬
suming BLV-positive colostrum (Fig. VI-4), for dam status
(Fig. VI-5), for breed (Fig. VI-6) and for dam parity
(Fig. VI-7). Lower rates of detection of BLV infection
were observed in young calves from infected dams and in
calves consuming colostrum from infected cows. Higher rates
of detection were observed in older Jerseys than in Holsteins
of the same age. Calves born to primiparous dams appeared
to have lower rates of detection through 18 months of age,
after which they began to experience higher rates of detec¬
tion until 27 months of age when rates were similar.
Significantly high factor correlations were found be¬
tween type of colostrum consumed and dam status (p=0.0001)
and between dam age and parity (p=0.0001), and low, but
significant, correlations were found between dam parity and
dam status (p=0.0001), between colostrum and parity (p=
0.001), and between colostrum and dam age (p=0.001) (Table
VI-3). High, negative correlation coefficients of estimated
parameters of survival were found only for dam age and
parity (r = -0.97) and for colostrum and dam status (r =
-0.86) (Table VI-4) .

60
Discussion
Throughout this study increasing or persisting antibody
titers to BLV, as measured by AGID-gp, were interpreted as
evidence for BLV infection. Because this method indirectly
tests for presence of virus by an immune response, some as¬
sumptions regarding sensitivity and specificity of the
diagnostic criteria should be made.
The BLV-gp antigen appears to be unique, since no cross
reactivity with proteins of other oncoviruses or retro¬
viruses has been demonstrated (Ferrer, 1972; Ferrer et al.,
1975; Kaaden et al., 1977; McDonald and Ferrer, 1976;
McDonald et al., 1976). A positive serologic response to
BLV-gp, therefore, can be considered specific for BLV.
Comparisons of several serologic tests have demonstrated
that AGID-gp is a relatively sensitive serologic test (Burny
et al., 1980). These results are corroborated by experi¬
mental studies in which a serologic response following BLV
inoculation was consistent (Miller et al., 1972; Schmidt
et al., 1976; Van Der Maaten and Miller, 1978b; Van Der
Maaten et al., 1981a) and persistent (Miller and Van Der
Maaten, 1976b). Similarly, BLV has been readily detected
from seropositive but not seronegative animals following
natural infection (Ferrer et al., 1976, 1977a, 1977b;
Olson et al., 1973; Piper et al., 1979).
There is no evidence for recovery from BLV infection.
On the contrary, seropositive cattle older than six months

61
appear to maintain detectable antibodies throughout life
(Chander et al., 1978; Kaaden et al., 1978; Tabel et al.,
1976). In a study to examine vaccine efficacy, inactivated
BLV produced only a transient serologic response, and virus
was not isolated (Miller and Van Der Maaten, 1978b). In
that study two doses of killed virus were required to induce
a serologic response. This suggests that persistent anti¬
body titers only result from active, persistent infection
and that any transient serologic response resulting from
exposure to a killed virus is rare.
Until recently, it could not be stated that absence of
either virus or antibody implied absence of specific BLV
sequences in host cell genomes. Studies now suggest that
such sequences are not to be found in cattle without BLV or
specific BLV antibodies (Callahan et al., 1976; Deschamps
et al. , 1981; Kettmann et al., 1976).
A final demonstration of the sensitive nature of AGID
using gp-51 lies in results of BLV-eradication programs
based upon mass screening with this test. Results of these
campaigns indicated that the virus was efficiently removed
from a herd by test-and-slaughter methods (Mammerickx et al.,
1978a; Schmidt et al., 1978, Straub, 1978b) . If AGID were
not an efficient discriminator of infected and noninfected
cattle, it is unlikely that eradication efforts would have
met with such rapid success. Use of AGID-gp to detect BLV
infection, therefore, is justified, particularly in a design

62
in which animals can be followed for several months and
persisting titers can be observed.
Survival analysis and life-table methods are well es¬
tablished techniques in epidemiology and actuarial science
(Gross and Clark, 1975; Lilienfield, 1976). Recently these
methods have seen increased application in veterinary
epidemiology (Cobo-Abreu et al., 1979; Hird et al., 1975;
Schwabe et al., 1977). Survival analyses are especially
appealing in prospective studies where animals lost to
follow-up can be considered in computations up to the time
of censoring, assuming failure rates similar in censored
and uncensored animals.
Data presented in this study are particularly suitable
for examination by survival methods for two reasons. First¬
ly, recovery from BLV infection is unknown and animals can
be defined as truly failed once infection is detected.
This is analogous to death in traditional applications.
Secondly, since these methods incorporate the dimension of
time, either by comparing distributions over time or by
using time as a dependent variable, they are appropriate
in studies of BLV infection because prevalence rates are
known to be associated with age (Burridge et al., 1979,
1981; Chander et al., 1978; Evermann et al., 1980; Ferrer
et al. , 1976; Mammerickx et al., 1978a, 1978b; Marin et
al. , 1978; Olson et al., 1973 ; Piper et al., 1979).
Cox's model was used to test estimated parameters of
a survival function where the underlying assumption was

63
that hazard rates were proportional (Cox, 1972; Taulbee,
1979). The model tends to force nonparallel curves to a
parallel model. Thus, interaction, characterized by cross¬
ing or bellying curves, could not be examined. Inclusion
of the zt variable removes dependence on proportionality and
allows for tests of interactions with age (Taulbee, 1979).
Estimated age-specific prevalence rates were calculated
as one minus the proportion remaining negative for BLV in¬
fection. The prevalence rate estimate for 18-month-old
cattle of 25% was lower than that of 45% described from a
cubic polynomial curve fitted to data collected from the
same herd for the years of 1975 through 1977 (Burridge
et al., 1979). Transmission rates of BLV infection, there¬
fore, appeared to have declined over the past four to five
years, at least in animals up to 18 months of age. This
may suggest variations of prevalence rates in yearly birth
cohorts, as found in other prospective studies (Huber et al.,
1981; Wilesmith et al., 1980). In those studies, it was
observed that cattle born in a given year experienced a
different life-time prevalence rate than did animals born
in some other year. Furthermore, the prevalence rate
within a cohort did not change appreciably beyond two
years of age. A similar situation may have occurred in
this herd due to management of Holstein heifers. Prior to
1977, bred Holstein heifers were kept in the dry herd until
shortly before calving. In the past few years, these
heifers have been managed separately from the dry herd,

64
whenever pasture space permitted, in order to provide them
with a better plane of nutrition. In this study Holstein
heifers were exposed to the dry herd for a relatively short
time, January through April 1981, which could have limited
BLV transmission and resulted in the lower prevalence rates.
Inspection of the overall life table revealed heavy
censoring during the first two to three months. This was
due to sales of bull calves and to neonatal mortality.
Early postnatal detection of BLV infection, constituting
the second detection phase, could have been represented by
calves infected in útero and not sampled precolostrally or
infected too late in gestation for antibodies to appear by
birth, as previously suggested (Van Der Maaten et al.,
1981b). Evidence that postnatal infection occurred during
this period was demonstrated by detection of infection in
calves born to noninfected dams.
The length of this period of detection would not cor¬
respond to the length of an underlying infection period
because of the seroconversion lag time (CHAPTER VIII) and
possible repression of viral expression by colostral anti¬
bodies. Inhibition of release of BLV by antibodies has
been demonstrated in vitro (Driscoll et al., 1977) and also
suggested in studies of colostral antibodies (Van Der Maaten
et al., 1981a). Antigenic modulation or inhibition of P
proteins (Sissons and Oldstone, 1980) may explain such a
phenomenon. The process of modulation is believed to
involve a binding of viral glycoprotein on the cell membrane

65
by circulating antibodies. Glycoprotein surface markers
become masked from recognition by K cells or other cells
invoking an antibody dependent cytotoxic response. A
failure to recognize virus-bearing lymphocytes by the
immune system renders them resistant to immune damage. If
antibodies are removed, for instance through natural at¬
trition of gammaglobulins, the lymphocyte would regain the
ability to shed virus. Inhibition of P proteins may also
be involved in repressing virus expression by inhibiting
transcription.
A further delay in detection, beyond the two- to three-
month seroconversion period and one-month sampling interval
could have resulted from early sampling-design flaws. As
much as a two-month delay could have occurred as a result
of the three-month sampling interval used at the beginning
of the study. It is likely, therefore, that infection
represented by this phase of detection occurred in the
first two to three months of life or even prenatally.
Several factors may have contributed to postnatal
transmission in the first two to three months. Calves may
have become infected at parturition when a calf born to an
infected dam ingested maternal blood from uterine or vaginal
tears (Van Der Maaten et al., 1931b). Rates of detection
in calves from infected dams, at least during the first
three months, however, were not different from rates in
calves from noninfected dams. Such a similarity of rates
may be an artifact due to delayed expression of the virus

66
by colostral antibodies. Consumption of colostrum with
BLV antibodies, therefore, may complicate control efforts
by masking early infection.
Type of calf management also may have influenced BLV
transmission during the first few months of life. Most
calves were placed inside the calf barn where they could
have been exposed to infected calves in adjacent pens.
Transmission may have resulted from ingestion or inhalation
(Van Der Maaten and Miller, 1978c) of saliva (Ressang et al.,
1980), urine (Gupta and Ferrer, 1980), blood (Mammerickx
et al., 1980; Van Der Maaten et al., 1981a), or lymphocytes
(Miller and Van Der Maaten, 1978b; Van Der Maaten and
Miller, 1978b, 1978c, 1981a). Animals were also tattooed
while in the barn, introducing the opportunity for iatro¬
genic transmission. Other calves occupied reasonably iso¬
lated pens outdoors, and they may not have experienced the
same risks of infection as indoor calves. Risks for animals
in various locations are examined further in CHAPTER VIII.
A third relatively quiescent phase of detection of BLV
infection between 6 and 15 months of age coincided with
movement of animals from densely occupied paddocks to
fields and pastures (APPENDIX D, Fig. 7). It also was noted
that vaccinations for other infectious diseases were given
either shortly before or during this period. Iatrogenic
transmission of BLV, therefore, does not appear to have
been of major importance in transmission because rates of
detection actually declined during this period. A more

67
detailed examination of detection rates and vaccination pro¬
cedures is presented in CHAPTER VII.
A sharp increase in detection rates typified the fourth
and last observed phase which began after 15 months of age.
The only management interventions preceding the increased
rates were insemination and movement of bred heifers to the
dry herd. Infection as a result of close physical contact
has been suggested as the major mode of BLV transmission
(Dechambre et al. , 1968; Maas-Inderwiesen et al. , 1978;
Straub, 1971, 1978a; Miller and Van Der Maaten, 1978a;
Wilesmith et al., 1980). Other reports mentioned similar
observations or seroconversions following exposure to in¬
fected animals (Ferrer et al., 1976; Piper et al., 1979).
However, in our study not all bred heifers entered the dry
herd, permitting a comparison of risks of two types of
heifer management in CHAPTER VIII.
It is not likely that transmission resulted from in¬
semination, since the exogenous nature of BLV excludes
transmission via gametes. This has been confirmed by
observational studies which did not find increased infec¬
tion rates in animals sired by BLV-infected bulls (Baum-
gartener et al., 1978) and by experimental studies which
failed to transmit BLV with semen from BLV-infected, but
otherwise healthy, bulls (Miller and Van Der Maaten, 1979;
Ressang et al., 1980). Furthermore, the time from breeding
(13-16 months of age) to peak rates of detection (18-21
months of age) was longer than suggested by experimental or

68
natural transmission studies (Gentile and Rutili, 1978 ;
Mammerickx et al., 1980; Straub, 1978b; Van Der Maaten and
Miller, 1978a, 1978b). Unfortunately, an effect of in¬
semination on transmission could not be examined further
because BLV status of sires was unknown and analysis would
have been confounded by the presence of only bred heifers
in the dry herd.
In the examination for associations between hazard
rates and dam age, dam parity, dam status, breed, and colos¬
trum type using Cox's model, no significant main effects
were observed. Results of Taulbee's alternative procedure,
however, suggested significant departures from proportional
hazards. The sizes of the differences detected by this al¬
ternative method are not known, and they may be too small
to be of practical importance in the control of BLV in¬
fection. Conclusions regarding the practical significance
of interactions, therefore, should be very tentative, but
discussion can be based on inspection of survival curves.
Graphical examination is meaningful because crossing of
survival curves cannot occur without crossing of hazard
curves, thus allowing for visual inspection of factor-by¬
age interaction.
Interactions between age and dam status and between
age and colostrum have already been discussed and indicated
that calves which consume colostrum from an infected cow or
which were born to a seropositive dam were protected from
detection but not necessarily infection, at an early age.

69
These two factors would be expected to have similar curves
because of the high negative correlation of their estimated
survival parameters. Although several factors were sig¬
nificantly correlated with each other, only dam parity and
dam age, and dam status and colostrum were correlated when
hazard rates of detection were considered.
An interaction of breed by age was suggested when old
Jersey heifers were observed to have higher rates of detec¬
tion than old Holstein heifers, but at young ages curves were
similar. It has been reported that Jerseys have low levels
of circulating gammaglobulins (Logan et al., 1981), but
this would not necessarily explain increased susceptibility
only in old Jersey heifers. A more reasonable explanation
for lower survival rates in old Jersey heifers is that they
remained in the dry herd until shortly before calving.
Holstein heifers, on the other hand, were removed from the
dry herd on about May 1, 1981, and Holsteins bred 45 days
prior to that time were never in the dry herd. The breed-
by-age interaction, therefore, was due most likely to
longer exposure of Jerseys to older, infected cattle in
the dry herd.
There has been no mention made in the literature of
dam parity or dam age effects on subsequent BLV infection
of progeny. Crossing of survival curves of animals from
primiparous and multiparous dams observed in this study
suggests an age-by-parity or age-by-dam age interaction.
Whether the crossing of these curves represents expected

70
variation, especially with small numbers at older ages, or
a real effect cannot be stated. No other explanation can
be provided.

Table VI-1
Life table and survival analysis of detection of bovine leukemia virus
infection.
Number of
animals
Proportion
Age
Interval
(days)
Entéred
Withdrawn
Detected
At-risk
Detected
Surviving
Cumulative
survival (S.E.)
Hazard
(S.E.)
0- 30
473
158
9
394.0
0.023
0.977
1.0
(0.0)
0.0008
(0.0003)
30- 60
306
29
1
291.5
0.003
0.997
0.9772
(0.0075)
0.0001
(0.0001)
60- 90
276
18
5
267.0
0.019
0.981
0.9738
(0.0082)
0.0006
(0.0003)
90-120
253
18
6
244.0
0.025
0.975
0.9556
(0.0114)
0.0008
(0.0003)
120-150
229
7
1
225.5
0.004
0.996
0.9321
(0.0146)
0.0001
(0.0001)
150-180
221
18
4
212.0
0.019
0.981
0.9279
(0.0151)
0.0006
(0.0003)
180-210
199
21
6
188.5
0.032
0.968
0.9104
(0.0172)
0.0011
(0.0004)
210-240
172
5
0
169.5
0.0
1.0
0.8815
(0.0203)
0.0 .
(0.0)
240-270
167
8
0
163.0
0.0
1.0
0.8815
(0.0203)
0.0
(0.0)
270-300
159
11
1
153.5
0.007
0.993
0.8815
(0.0203)
0.0002
(0.0002)
300-300
147
10
0
142.0
0.0
1.0
0.8757
(0.0210)
0.0
(0.0)
330-360
137
9
2
132.5
0.015
0.985
0.8757
(0.0210)
0.0005
(0.0004)

Table VI-1
Continued
1
Number of
animals
Proportion
Age
Interval
(days)
Entered
Withdrawn
Detected
At-risk
Detected
Surviving
Cumulative
survival (S.E.)
Hazard
(S.E.)
360-390
126
15
0
118.5
0.0 ,
1.0
0.8625
(0.0226)
0.0
(0.0)
390-420
111
12
2
105.0
0.019
0.981
0.8625
(0.0226)
0.0006
(0.0005)
420-450
97
11
1
91.5
0.011
0.989
0.8461
(0.0250)
0.0004
(0.0004)
450-480
85
12
0
79.0
0.0
1.0
0.8368
(0.0264)
0.0
(0.0)
480-510
73
1
3
72.5
0.041
0.959
0.8368
(0.0264)
0.0014
(0.0008)
510-540
69
2
5
68.0
0.074
0.926
0.8022
(0.0320)
0.0025
(0.0011)
540-570
62
3
3
60.5
0.050
0.950
0.7432
(0.0390)
0.0017
(0.0010)
570-600
56
3
5
54.5
0.092
0.908
0.7064
(0.0425)
0.0032
(0.0014)
600-630
48
5
3
45.5
0.066
0.934
0.6415
(0.0475)
0.0023
(0.0013)
630-660
40
5
2
37.5
0.053
0.947
0.5992
(0.0502)
0.0018
(0.0013)
660-690
33
8
2
29.0
0.069
0.931
0.5673
(0.0524)
0.0024
(0.0017)
690-720
23
12
0
17.0
0.0
1.0
0.5282
(0.0556)
0.0
(0.0)
720-750
11
4
1
9.0
0.111
0.889
0.5282
(0.0556)
0.0039
(0.0039)
750-780
6
3
1
4.5
0.222
0.778
0.4695
(0.0742)
0.0083
(0.0083)
780-810
2
2
0
1.0
0.0
1.0
0.3652
(0.1086)
0.0
(0.0)

Table VI-2. Results of survival analysis of detection rates of bovine
leukemia virus infection.
Variable
Values of variable
Chi Square
Variable by age*
(1 d.f.)
Variable alone
Dam parity
0,1
70
(P
< 0.0001)
0.10
(p = 0.75)
Dam age (months)
20-120
79
(P
< 0.0001)
0.07
(p = 0.79)
Dam status
0,1
35
(P
< 0.0001)
0.54
(p = 0.46)
Colostrum
0,1
55
(P
< 0.0001)
0.45
(p = 0.50)
Breed
0,1
85
(P
< 0.0001)
0.03
(p = 0.86)
*
Age at detection.

Table VI-3. Correlation coefficients of factors examined for association with
infection with bovine leukemia virus (BLV).
Factor
Factor
Dam BLV status
Dam age
*
Colostrum
Breed
Dam parity
0.30 (0.0001)+
n = 473
0.68 (0.0001)
n = 470
0.18 (0.001)
n = 332
-0.07 (0.11)
n = 473
Dam BLV status
0.27 (0.0001)
n = 471
0.81 (0.0001)
n = 333
0.07 (0.15)
n = 474
Dam age
0.18 (0.001)
n = 333
-0.05 (0.29)
n = 471
4^
★
Colostrum
0.14 (0.013)
n = 333
*
Refers to calves consuming colostrum with BLV antibodies.
+Figure in parentheses is the probablility >|R
under Ho: R = 0.

75
Table VI-4. Correlation coefficients of estimated parame¬
ters of hazard rate functions for the detection
of bovine leukemia virus infection.
Variable
Variable
Dam status
Dam age
Colostrum
Breed
Dam parity
-0.002
-0.973
0.027
0.087
Dam status
-0.027
-0.857
-0.021
Dam age
-0.036
-0.052
Colostrum
-0.037

76
Fig. VI 1. Estimated age-specific cumulative survival
(%) and prevalence rate (%) of detection of
bovine leukemia virus infection.

HAZARD RATE (%) OF DETECTION
OF BLV INFECTION
77
Fig. VI-2. Age-specific hazard rates of detection of
bovine leukemia virus (BLV) infection.

78
20 -i
u —
Hi
Z < 10 -
T S
> z
T
3
"1 I I I 1 1 1
6 9 12 15 18 21 24 27
AGE (MONTHS) AT DETECTION
Fig. VI-3. Age at detection of bovine leukemia virus (BLV)
infection for 63 BLV-infected animals.

CUMULATIVE PROPORTION REMAINING
UNDETECTED FOR BLV
79
AGE (DAYS)
Fig. VI-4. Cumulative proportion of calves consuming colos¬
trum with bovine leukemia virus (BLV) antibodies
and of calves not consuming colostrum with BLV
antibodies remaining undetected for BLV infec¬
tion .

80
CALVES BORN FROM
BLV-INFECTED DAMS
Fig. VI-5. Cumulative proportion of animals from bovine
leukemia virus (BLV)-infected dams and from
noninfected dams remaining undetected for
BLV infection.

81
Fig. VI-6. Cumulative proportion of Holsteins and Jerseys
remaining undetected for bovine leukemia virus
(BLV) infection.

CUMULATIVE PROPORTION REMAINING
UNDETECTED FOR BLV INFECTION
82
AGE (DAYS)
Fig. VI-7. Cumulative proportion of animals born to primi-
parous cows and of animals born to multiparous
cows remaining undetected for bovine leukemia
virus (BLV) infection.

CHAPTER VII
SEASONAL PATTERNS OF RATES OF BOVINE LEUKEMIA
VIRUS INFECTION
Introduction
A fundamental consideration in the epidemiology of in¬
fectious diseases is the examination for temporal patterns
of occurrence of a disease. Seasonal or secular trends in
incidence rates may suggest modes of transmission, causal
associations, and/or etiologic agents. If, for example, a
hypothesized factor in disease transmission demonstrates
seasonal variability, and a statistically significant season
al cycle of disease exists in phase with the hypothesized
factor, then supporting evidence favoring involvement of
the factor in transmission has been demonstrated. On the
other hand, if no seasonal occurrence of disease can be
demonstrated, or it is not in phase with that of the factor,
then the hypothesis of factor association should be rejected
Interest in possible vector-borne transmission of BLV
has arisen from evidence for arthropod involvement in the
spread of another retrovirus, equine infectious anemia virus
(Fischer et al. , 1973; Hawkins et al., 1973a, 1973b). Re¬
ports based on experimental and observational data have
suggested the involvement of arthropod vectors in BLV trans¬
mission (Bech-Nielsen et al., 1978; Ohshima et al., 1981).
83

84
Another study, however, revealed higher rates of infection
during winter months, coinciding with crowded, indoor hous¬
ing conditions rather than exposure to large numbers of
flies (Wilesmith et al., 1980).
In this chapter, the hypotheses tested are as follows:
(1) age-specific rates of detection of BLV infection do
not differ with respect to month of birth; (2) rates of
detection of BLV infection show no significant seasonal
pattern associated with the seasonal frequency of potential
arthropod vectors; and (3) no other seasonal pattern of
rates of detection exists.
Materials and Methods
Month of Birth
Cox's hazard model described in CHAPTER VI was used to
examine for an association between month of birth and sub¬
sequent BLV infection. Month of birth was denoted by z in
the model. Detection of BLV infection was based on cri¬
teria presented in CHAPTER VI.
Month of Detection of BLV Infection
Monthly incidence rates of detection of BLV infection
were computed to estimate seasonal patterns of BLV infec¬
tion rates. Monthly incidence rates of detection were cal¬
culated as the number of animals detected during the month
divided by the number of animals at risk of being detected

85
in that month. The criteria for an animal to be at risk for
any month of follow-up were (1) the animal must not have
been detected previously; (2) the animal must have been
present for at least half of a month; (3) an animal born in
the last half of a month was considered only in subsequent
months; and (4) an animal remaining undetected for more
than one year would be considered also for each repeated
month. For example, if an animal were present during
January 1980, and January 1981, it would be counted as
two animals-at-risk during the month of January. Those
animals detected as infected during a month also were
counted in the at-risk denominator.
Possible differences between the 12 monthly incidence
rates were examined using a Chi Square test with 11 degrees
of freedom. In order to determine if monthly incidence
rates followed a simple harmonic trend, a test for goodness-
of-fit of the data to a simple harmonic curve was performed
using a Chi Square statistic, as previously described
(Walter and Elwood, 1975). The test for a simple harmonic
trend of incidence rates, however, could not be pursued
2
because a high Chi Square value (X ^ = 17.5, 0.05 indicated that these rates were inappropriately described
by a simple harmonic curve.
An alternate, nonparametric approach to the seasonality
of events was used to examine for six-month trends in in¬
cidence rates (Hewitt et al., 1971) Rates were computed
only for animals over 12 months of age. The tested

86
hypothesis stated that six-month cumulative ranks of inci¬
dence rates from May through October, the fly season, were
not greater than those for the 11 other six-month periods.
A second hypothesis was tested for no differences in cumu¬
lative ranks of incidence rates for any nonspecified six-
month period.
Results
Month of Birth
No significant differences were found between hazard
rates of detection of BLV infection for animals born in
each of the 12 months (p = 0.24). The proportion of animals
infected was highest in animals born in August, September,
and October (Fig. VII-1).
Month of Detection of BLV Infection
No significant differences were found between the 12
2
monthly incidence rates (X^^ = 9.81, 0.4 The numbers of animals detected as BLV infected and at
risk of detection for each of the 27 months of observation
are presented in Table VII-1. Monthly incidence rates of
detection for animals of all ages ranged from 1.1% in
January and April to 3.0% in June (Fig. VII-2). For ani¬
mals over 12 months of age, cumulative ranks of monthly
incidence rates between May and October were not signifi¬
cantly greater than those for any other six-month period

87
(p = 0.20) (Table VII-2). Cumulative ranks of monthly in¬
cidence rates were highest for the six-month period be¬
ginning with March and were lowest for the period beginning
with September. The probability of cumulative ranks was
lowest for the period beginning with March, but this was
not significant without an a priori commitment (p=0.13).
Discussion
Although no statistical significance could be placed
on differences between birth-cohort hazard rates, calves
born between August and October constituted 65% of the in¬
fected animals, even though only 42% of calves were born
during that period (APPENDIX C). This was not surprising
for several reasons. The density was highest during the
period in which these calves were in the calf barn
(CHAPTER III). In a crowded situation, transmission may
occur either by aerosol (Van Der Maaten and Miller, 1978c)
or by contact (Dechambre et al., 1968; Maas-Inderwiesen
et al., 1978; Miller and Van Der Maaten, 1978a; Straub,
1971, 1978a; Wilesmith et al., 1980). Also, since these
animals were the oldest in the study, they had a greater
chance of entering the dry herd where there may have been
an increased risk of infection due to contact with older,
BLV-infected cattle. Calves born during the winter and
spring were too young to be bred and enter the dry herd by
May 1981. The proportion of calves born in the spring and

88
subsequently becoming infected would be expected to be low
because few cows calved at that time (APPENDIX C).
Two assumptions were made in the analysis of monthly
incidence rates of detection of BLV infection. One was
that animals were considered independent within and among
months followed. This is reasonable because exposure to
a possible BLV-carrying insect and susceptibility to BLV
infection were not likely to be related to any previous
experience.
The other assumption in examination of monthly inci¬
dence rates was that any pattern of detection would be
synchronized with that of infection and would consistently
follow infection by two to three months. This assumption
may not be valid for calves less than six months of age.
Infection may occur in útero or shortly before birth but
before acquisition of passive protection from colostral
antibodies. In such cases, detection of infection may not
be made for six months or more because virus repression may
be dependent on both antibody and virus concentration
(Driscoll et al., 1977; Straub, 1978a). It is believed,
however, that viral expression would appear within 12
months of infection (Van Der Maaten et al., 1981a).
Analysis of possible vector transmission also may have
been confounded by calfhood management. Since the calving
season occurred during the summer and early fall, animal
density in the calf barn was highest during late summer and
fall. Seroconversion of animals several months later could

89
be interpreted as infection resulting from close physical
contact rather than from arthropod vectors. Furthermore,
the risk of infection for calves in the calf barn may not
have been as high as for those over one year of age. Flies
found in the calf barn were not usually the biting type,
and sporadic insect control was practiced, which limited
exposure to potential vectors. Colostral antibodies also
may have provided some resistance to infection from small
doses of virus introduced by an insect (Van Der Maaten
et al., 1981a).
The situation with cattle more than 12 months of age
was quite different. Biting flies were present on these
animals throughout summer months, and no fly control was
practiced. Prevalence rates of infection also were higher
in these animals (CHAPTER VI), increasing the chance that
a fly would first feed on an infected animal. Cattle over
one year of age, therefore, were analyzed separately as they
constituted a more susceptible and exposed population to
possible vector-borne transmission and because infection
was more easily detected and analysis was not confounded
by management factors.
Results of the Chi Square test indicated that there
were no significant differences between monthly incidence
rates. Important seasonal trends, however, may be present
without apparent rate differences between months (Walter
and Elwood, 1975). The method proposed for analysis of
seasonal trends in incidence rates (Edwards, 1961; Walter

90
and Elwood, 1975) was particularly appealing because season¬
al frequencies of potential arthropod vectors in temperate
and subtropical climates generally resemble simple harmonic
curves which peak during summer months (Beck, 1958; Blanton
and Wirth, 1979; Bohart and Washino, 1978; Jones and Anthony,
1964; Khalaf, 1969). Their analysis could not be pursued
because the incidence rates were inappropriately described
by a simple harmonic curve. The goodness-of-fit test in¬
dicated that incidence rates did not resemble a simple har¬
monic curve and no further tests for significance or maximum
amplitude of a curve should be performed. This analytic
method also could not be used to test rates in older animals
because the recommended sample size is not less than 50
(Walter and Elwood, 1975) . Instead, a nonparametric method
appropriate for small samples was used to examine for ex¬
cessive rates over six-month periods (Hewitt et al., 1971).
Difficulties with Hewitt's alternative procedure have
been its lack of power and inability to estimate parameters
of an harmonic curve (Walter and Elwood, 1975). In spite
of these restraints and the few infections detected, a
marked tendency for maximum risk of detection of infection
was revealed between March and August (p=0.13), the six-
month period beginning with March. Had an a priori hypothe¬
sis been specified for that particular yearly segment, there
would be reason to believe that an excessive rate of de¬
tection had occurred during that period (p = 0.01). This
interval would coincide with infection resulting from

91
exposure to animals in the dry herd between January and May
1981. If vectors had played a major role in transmission
and assuming peak infection around July, then maximum
cumulative ranks of incidence rates of detection should
have been observed between May and October. This was not
the case, as indicated by acceptance of the hypothesis of
no increase in incidence rates for that six-month period.
Results of this study are consistent with those from
a study in which increased rates of seroconversion were ob¬
served after cattle grazed together on summer pastures
(Onuma et al., 1980). In that study, arthropod-borne
transmission could not be examined because analysis would
be confounded by congregation of cattle only during the
vector season. In another study, two groups were compared
for rates of infection during winter and summer months
(Bech-Nielsen et al., 1978). Rates observed for summer
and winter groups, 4/7 and 1/7, respectively, could have
occurred by chance (Fisher's exact p = 0.13). A study of
incidence rates of BLV seroconversion in a large dairy
found higher rates in winter and spring, implying trans¬
mission associated with crowded housing (Wilesmith et al.,
1980). None of these studies examined monthly rates for a
complete seasonal cycle. Future studies of seasonal patterns
of disease should be based on at least two years of monthly
cohort data in an attempt to remove as much year-effect as
possible.

92
Experimental studies have attempted to examine poten¬
tial horsefly transmission of BLV. After finding BLV in
the midgut of Tabanus nigrovitatus, it was concluded that
fly control may reduce transmission rates (Bech-Nielsen et
al., 1978). However, horseflies are interrupted and in¬
efficient feeders and only transmit disease agents mech¬
anically via their mouthparts (James and Harwood, 1979).
Presence of BLV in the midgut of a tabanid probably provide
little evidence that these flies are natural vectors of BLV
Another study which used various species of horseflies
demonstrated transmission of BLV to sheep (Ohshima et al.,
1981). Flies which had fed on an infected cow were manu¬
ally transferred to noninfected sheep and held on the sheep
for as many as 140 feedings in four days. Although proving
that horseflies can transmit BLV to an unnatural host, the
question remains concerning the extent to which these flies
transmit BLV infection to cattle under natural conditions.
Circumstantial evidence favors the hypothesis that
vectors do not contribute significantly to BLV transmission
Beef herds have much lower BLV-infection rates than dairy
herds (Baumgartener et al., 1975; Burridge et al., 1981;
House et al., 1977). Fly control usually is more intense
in dairy than beef herds partially because of milk sanita¬
tion requirements. If biting flies were important in
transmission, these differences between rates probably
would not be observed.

93
Incidence rates of detection of BLV infection observed
in cattle over 12 months of age suggested no association
with frequencies of potential arthropod vectors. Trends in
incidence rates were suggestive of a management procedure,
however, specifically that of moving heifers into a popula¬
tion of older, infected cattle. Therefore, special atten¬
tion should be paid to management interventions whenever
examining seasonal rates of animal infections.

Table VII-1. Numbers of animals detected as infected with bovine leukemia virus and
numbers at risk of detection for each month of observation.
Year Month
Number
at risk
Number
detected
Incidence
rate (%) Year Month
Number
at risk
Number
detected
Incidence
rate (%)
1979 July
2
0
0
1980 Aug
127
1
0.8
Aug
8
0
0
Sept
150
0
0
Sept
39
0
0
Oct
166
3
1.8
Oct
64
0
0
Nov
178
4
2.2
Nov
85
3
3.5
Dec
186
1
0.5
Dec
71
2
2.8
1981 Jan
199
1
0.5
1980 Jan
80
2
2.5
Feb
205
3
1.5
Feb
79
1
1.3
Mar
199
4
2.0
Mar
85
3
3.5
Apr
182
3
1.6
Apr
84
0
0
May
179
4
2.2
May
86
1
1.2
June
177
8
4.5
June
88
0
0
July
158
4
2.5
July
108
0
0
Aug
145
4
2.8
Sept
135
2
1.5

Table VII-2. Monthly incidence rates of detection of bovine leukemia virus infection in
animals between 12 and 27 months of age.
Month
Number
detected
(1)
Number
at risk
(2)
Incidence
rate (%)
(1) l (2)
Rank of
incidence
rate
Cumulative ranks
for next
six months
k
Probability
Any six- Specified
month six-month
segment segment
Jan
0
55
0
1.5
45.5
0.87
0.18
Feb
2
63
3.17
7
49.0
0.50
0.07
Mar
3
67
4.47
9
53.0
0.13
0.01
Apr
3
66
4.54
10
47.0
0.73
0.12
May
2
65
3.08
6
45.0
0.91
0.20
June
6
62
9.68
12
43.0
0.99
0.29
July
2
72
2.78
5
32.5
1.00
1.00
Aug
4
81
4.94
11
29.0
1.00
1.00
Sept
1
91
1.10
3
25.0
1.00
1.00
Oct
1
31
3.23
8
31.0
1.00
1.00
Nov
1
41
2.44
4
33.0
1.00
1.00
Dec
0
50
0
1.5
35.0
1.00
1.00
k
From Hewitt et al., 1971.

96
Fig. VII-1. Percentage of 54 animals infected with bovine
leukemia virus born in each of the 12 months
of the year.

INCIDENCE RATE (%) OF DETECTION OF
BLV INFECTION
97
Fig. VII-2. Monthly incidence rates (%) of detection of
bovine leukemia virus (BLV) infection in 54
animals. Figures above bars are the number
of animals detected divided by the number of
animals at risk.

CHAPTER VIII
SPATIAL PATTERNS OF BOVINE LEUKEMIA VIRUS INFECTION
Introduction
In previous chapters, patterns of BLV infection were
studied by examining age or temporal trends in detection of
BLV infection. Assuming servoconversion actually occurred
within about two months of infection, infection patterns
could be examined by a two-month temporal adjustment in
detection rates. Age-specific rates and seasonal patterns
of detection both suggested a strong association between
infection and exposure to the dry herd. A common location
at infection, however, may become obscured as animals move
through various pastures, thus making it difficult to ex¬
amine for a hypothesized spatial component of transmission.
An animal, therefore, may have been detected as infected in
the dry herd when it was actually infected in some prior
location.
Another aspect of spatial associations concerns trans¬
mission of BLV infection in the calf barn. Calves may have
occupied a pen adjacent to an infected calf, possibly in¬
creasing the risk of infection through imposed close
contact.
The intent of this chapter is two-fold. Firstly, a
hypothesis is tested which states that, while in the calf
98

99
barn, rates of detection do not differ between calves penned
adjacent to calves infected in útero and calves not in
adjacent pens. Secondly, to assess risk of BLV infection
at various locations, weighted expected probabilities of
BLV infection are derived using a seroconversion function
employing results from experimental studies.
Materials and Methods
Risk of BLV Infection from Exposure to Calves
Infected In Utero
Calves known to be infected while in the calf barn were
the eight calves previously identified as infected in útero
(CHAPTER IV). Calf H949 also was included in this group
because of evidence of in útero or very early postnatal in¬
fection (Table V-l). Exposed animals were defined as
calves which had been located adjacent to any of the nine
calves mentioned above while in the calf barn. Evidence for
BLV infection in exposed and nonexposed calves was based on
criteria established in CHAPTER VI. A hypothesis of no
association between exposure to the nine infected calves
and subsequent infection was tested using Fisher's exact
test from STATPAK of MUSIC. Associations were examined for
the average number of calves followed for six months and for
the average number followed for twelve months. Averages
were computed by dividing by two the sum of the number of
calves beginning the follow-up period and the number present
at the end of the period.

100
Risks of BLV Infection in Five Types of Locations
Weighted expected probabilities of infection
A. Seroconversion function. From previously pub¬
lished data (Mammerickx et al., 1980; Van Der Maaten and
Miller, 1978a, 1978b), a seroconversion function was de¬
rived which described the probability of an animal having
BLV antibodies for each day following the experimental
inoculation of BLV. Cumulative proportions of animals
serologically positive were calculated for each day after
inoculation. By dividing the weekly proportions (differ¬
ences between consecutive weekly cumulative rates) by
seven, an expected daily proportion was obtained for that
52
week (Table VIII-1). Daily probabilities, {p.} , were
1 ¿=1
then derived from an approximated curve plotted through
these week midpoints (Fig. VIII-1), where the probability
of seroconversion by 52 days postinoculation was 0.9996
i 52
(Table VIII-2). Cumulative probabilities, {P. = E p„ } ,
1 1=1 i=l
were obtained by summation of the p .
X/
B. Algorithm for expected probabilities associated
with locations. Utilizing the cumulative function, P , an
algorithm was devised which examined location-specific
infection rates. The algorithm assigned fractions of in¬
fection to locations occupied by the infected animal prior
to detection of infection. These fractions were totaled
for each of five locations and divided by the animal-days
of occupancy to arrive at an expected rate of infection

101
for each location. These rates were then compared to
those based only on location at the time of detection of
infection.
Expected probabilities for each location were derived
by first computing the probability of infection for each of
the 52+k days prior to detection of an animal, given that
a negative test was observed k days prior to the positive
test (detection).
Two vectors, A and B, were defined such that
A= (A±} = (P1,P2,•••
k 52+k
where was the cumulative probability described above and
1 was the probability of infection for each of the k days
between the negative test and detection, and
B = Í B ± } = {1,1,^. . ■ ,1,1-P1,1-P2, . . . ,1-P52}
k 52+k
where 1-P^ was the cumulative probability of being infected
within i days prior to detection, and 1 was the probability
of being infected for each of the k days prior to the
negative test. Conditional probabilities were estimated by
52+k
AB = {A.B.}
— 1 1 i=l
and in turn were weighed by
52 t
1/ Z A.B. = 1/A B
i=l 11

102
to obtain the proper density function, where is the
transpose of the B vector. These functions would appear as
F(52+k) = {A B^/A Bfc = 0 ,
5 2+k
F(52+k-l) = Z {A.B.}/A B ,
i=52+k-l 1 1
F(l) = Z {A.B }/A Bfc ,
i=l
F (0) = 1.
Once density functions were defined for each animal,
I
fractions of infection, P., were allocated to each of j
locations according to time of occupancy in the 52+k days
prior to detection. Time was measured from detection such
that tj was the number of days from entering location j
until detection, where the location at detection was j =1
(Fig. VIII-2). Probabilities of an animal becoming infected
in each of j locations, for example, would be
p'± = F(0) - F(t ) ,
p'2 = F(t1) - F (t2) ,

103
p! = F(t. ) - F(t. ) .
D 3-1 3
Risks associated with locations
Locations, grouped by type of management, were calf
barn (indoor, outdoor, and combined), paddocks, calf unit,
heifer pastures, and dry herd. An estimated risk of infec¬
tion was calculated for a location by dividing the sum of
I
the P 's for that location by the animal-days of occupancy
in that location. Animal-days was calculated by summing
days spent in the location for each animal remaining un¬
detected for BLV infection. Rates of detection for each
location were calculated as the number of animals detected
in the location divided by the animal-days of occupancy.
Relative and attributable risks of expected infection
rates in locations were computed and probabilities of rela¬
tive risks equaling one were calculated as previously
described (Schwabe et al., 1977).
Location prevalence rates
A typical prevalence rate of BLV infection for the dry
herd was estimated from all cattle occupying the dry herd
between early January 1981 and September 30, 1981. The
rate was calculated as the number of BLV-seropositive cat¬
tle divided by the total number of animals occupying the
dry herd during that period. Prevalence rates for other
locations were estimated from the high range of age-specific

104
rates (Fig. VI-1) for the age group in each location
(CHAPTER III).
Results
Risk of BLV Infection from Exposure to Calves
Infected In Utero
No significant association was found between exposure
in the calf barn to calves infected with BLV in útero and
subsequent BLV infection detected either prior to six
months of age (p = 0.61) or prior to one year of age (p =
0.63) (Table VIII-3) .
Risk of BLV Infection in Five Types of Locations
The sum of weighted, expected probabilities of BLV
infection for each location for 53 infected animals is
presented in Table VIII-4. The estimated number of animals
infected per 10,000 animal-days at risk ranged from 2.26
in the calf unit to 29.39 in the dry herd (Table VIII-4).
Significantly high relative risks were associated with the
dry herd compared to the calf barn (0.0001 docks (0.001 pastures (p<0.001) (Table VIII-5). A significantly low
relative risk was associated with the calf unit compared
to the calf barn (p<0.05).
The number of infections per 10,000 animal-days at risk
attributed to the dry herd location ranged from 27.1

105
compared to the calf unit to 23.2 compared to the calf barn
(Table VIII-5).
Rates of detection of BLV infection in each of the
five location types is presented in Table VIII-6.
Location Prevalence Rates
A typical dry herd prevalence rate of BLV infection
was estimated to be 76%. Rates for the calf barn, paddocks,
calf unit, and heifer pastures were 5%, 12%, 12%, and 20%,
respectively.
Discussion
No increased risk of infection was observed in calves
penned next to calves infected in útero. Colostral anti¬
bodies may have repressed viral replication and subsequent
virus shedding due to immunologic modulation, as discussed
previously (CHAPTER VI). Some resistance to infection also
may have been offered to the noninfected calf by colostral
antibodies. As colostral antibodies decay, however, trans¬
mission of infection may be successful. The early detection
and isolation of infected calves, therefore, should be
encouraged.
Estimated relative and attributable risks presented a
clear indictment for exposure to the dry herd as a major
factor influencing BLV transmission. Further support was
provided for the hypothesis that physical contact is
necessary before transmission can take place (Maas-Inderwiesen

106
et al., 1978; Miller and Van Der Maaten, 1978a; Ferrer and
Piper, 1981; Wilesmith et al., 1980), because heifers in
pastures differed from those in the dry herd only by their
exposure to a lower prevalence rate of infection (20%
versus 76%).
Increased risk in the dry herd may have resulted not
only from exposure to a high percentage of infected cattle
but also from increased contact due to high animal density,
as suspected in another study (Wilesmith et al., 1980).
Similarly, the drop in risk associated with the calf unit
compared to the calf barn or paddocks may have represented
a reduction in animal density. Further examination of
interactions of prevalence rate and density on transmission
rates of BLV infection deserves attention, particularly in
establishing guidelines for BLV control.
Some quantitative guidelines for the use of five loca¬
tion types in heifer management were provided here by risk
estimates. It is shown, for instance, that heifers would
experience a risk of BLV infection in the dry herd over
five times that in heifer pastures. Over a three month
period (about 100 days), this would amount to 24 of 100
heifers infected due to exposure in the dry herd. Only a
slight protection from infection was associated with use of
outdoor calf pens. Because few calves occupied the outdoor
pens, numbers may be too small for practical comparisons.
These risk estimates could help set cost-effective
priorities in managing BLV infection in a dairy. They also

107
could be used to identify other sources of transmission by
focusing on reasons why locations are associated with dif¬
ferent risks of infection.
The algorithm presented here retrospectively partitions
the likelihood of an animal becoming infected with BLV,
starting from the time of detection. The estimated frac¬
tions of infection for any given time interval have two
components. One is the constant seroconversion function,
derived here from results of three experimental studies.
The other component is the time between tests, a variable.
Improvement in the validity of the algorithm, and thus
proportions estimated, could be made by improving either of
these components. The seroconversion function could be
refined by using rates of seroconversion from a large sample
of animals experimentally infected by a method simulating
natural infection (e.g., perhaps aerosol) and tested at
daily intervals. Further improvements in estimated propor¬
tions could be made by shortening the testing interval (k)
of animals under study, thus reducing the estimated period
of transmission. Methods for measuring bounds on the error
of these estimates also would be useful.
This technique could benefit studies of other diseases
in which infection precedes signs or symptoms by several
weeks or months. A measure of confidence would be provided
for infection in some time period prior to detection or
diagnosis of the disease.

108
More appropriate tests of hypotheses could be made for
factors observed during a period preceding detection rather
than for factors observed at the time of detection. This
was illustrated by the discrepancy between risks measured
at the time of detection of BLV infection and those esti¬
mated prior to detection. The latter method provided more
insight into infection occurring at young ages, as demon¬
strated by higher risks associated with the calf barn and
paddocks.

Table VIII-1. Summary of three studies on experimental infection with bovine
leukemia virus (BLV) from which probabilities for seroconversion
were derived as a function of days postinoculation with BLV.
Days after inoculation with
BLV
Study*
0
7
14
21
23
35
42
49
Number of animals
a
9
9
9
9
9
9
9
9
present
b
5
5
4
3
3
2
2
2
c
6
6
6
6
6
6
6
6
Total (1)
20
20
19
18
18
17
17
17
Number of animals
a
0
0
1
2
4
6
8
9
serologically
positive for BLV
b
0
0
0
0
0
1
2
2
c
0
0
0
1
3
4
6
6
Total (2)
0
0
1
3
7
11
16
17
Cumulative proportion
0
0
0.053
(3) = (1) t (2)
0.167 0.389 0.647
0.941
1.0
Weekly proportion (4)
0 0.053 0
.114
0.222
0.258
0
.294 0
.059
Daily proportion at midweek
(5) = (4) 1 7
*
0 0.0076 0
.0163
0.0317
0.0369
0
.0420 0
.0084
a. Van Der Maaten and Miller, 1978a.
b. Van Der Maaten and Miller, 1978b.
c. Mammerickx et al., 1980.
109

110
Table VIII-2. Daily and cumulative daily probabilities of
seroconversion to bovine leukemia virus (BLV)
following experimental inoculation with BLV.
Probability of seroconversion*
is t inoculation
Daily (p¿)
Cumulative daily (P^)
1
0.0
0.0
2
0.0
0.0
3
0.0
0.0
4
0.0003
0.0003
5
0.0011
0.0014
6
0.0018
0.0032
7
0.0028
0.0060
8
0.0039
0.0099
9
0.0051
0.0150
10
0.0063
0.0213
11
0.0073
0.0286
12
0.0088
0.0374
13
0.0101
0.0475
14
0.0114
0.0589
15
0.0130
0.0719
16
0.0146
0.0865
17
0.0162
0.1027
18
0.0179
0.1206
19
0.0197
0.1403
20
0.0216
0.1619
21
0.0233
0.1852
22
0.0251
0.2103
23
0.0267
0.2370
24
0.0286
0.2656
25
0.0302
0.2958
26
0.0318
0.3276
27
0.0332
0.3608
28
0.0348
0.3956
29
0.0358
0.4314
30
0.0367
0.4618
31
0.0377
0.5058
32
0.0385
0.5443
33
0.0392
0.5835
34
0.0400
0.6235
35
0.0404
0.6639
36
0.0408
0.7047
37
0.0411
0.7458
38
0.0416
0.7874
39
0.0418
0.8292
40
0.0393
0.8685
41
0.0328
0.9013
42
0.0257
0.9270

Ill
Table VIII-2. Continued.
Days postinoculation
Probability
of seroconversion*
Daily (pi)
Cumulative daily (P^)
43
0.0197
0.9467
44
0.0148
0.9615
45
0.0112
0.9727
46
0.0078
0.9805
47
0.0065
0.9870
48
0.0047
0.9917
49
0.0037
0.9954
50
0.0023
0.9977
51
0.0014
0.9991
52
0.0005
0.9996
k
Determined by AGID-gp in experimental studies (Mammerickx
et al., 1980; Van Der Maaten and Miller, 1978a, 1978b).

Table VIII-3.
Association of bovine leukemia virus infection (BLV) with exposure in
the calf barn to calves infected with BLV in útero.
Calves
followed for 6
months
Calves
followed
for 12
months
Number of calves
Number of
calves
Exposure of calves
Infected
Not infected
Total*
Infected
Not infected
Total*
In pen adjacent to
a calf infected
in útero
2 +
18
20
+
2"
14
16
In pen not adjacent
to a calf infected
in útero
22
203
225
26
161
187
*
Average number of calves followed in the follow-up period.
+Exact p = 0.61.
+
Exact p = 0.63.
112

Table VIII-4.
Estimated risk of infection with bovine leukemia virus (BLV) associated
with locations occupied by animals prior to detection of BLV infection.
Location type
Expected number
of animals infected (Ip!)
(1) D
Animal-days of
occupancy
(2)
Estimated risk of infec¬
tion (animals per 10,000
animal-days at risk)
(1) T (2)
Calf barn
indoor
10.57
16,729
6.32
outdoor
2.70
4,727
5.72
combined
13.28
21,456
6.19
Paddocks
3.09
5,280
5.85
Calf unit
6.46
28,658
2.26
Heifer pastures
20.25
38,518
5.26
Dry herd
9.92
3,376
29.38
53.00
113

Table VIII-5. Relative and attributable risks of infection with bovine leukemia virus
(BLV) estimated for five location types.
Location type
Location type
Calf barn
Outdoor
Paddocks
Calf unit
Heifer pastures
Dry herd
Calf barn
Indoor
0.91
(-0.6)*
Combined
0.95
(-0.3)
0.37 +
(-3.9)
0.85
(-0.9)
4.7 51
(23.2)
Paddocks
0.39
(-2.3)
0.90
(-0.6)
5.02*
(23.5)
Calf unit
2.33
(3.00)
13.00*
(27.1)
Heifer pastures
5.59*
(24.1)
•k
Figure in parentheses is estimated
attributable
risk (number
of BLV-infected
animals
per 10,000 animal-days at risk).
^Probability that relative risk = 1.0, p<0.05.
±0.0001 *0.01 *p<0.0001.
114

Table VIII-6. Risk of detection of bovine leukemia virus (BLV) infection associated
with locations occupied by animals at the time of detection.
Risk of detection
Animal-days of (number detected per
Location type Number detected occupancy 10,000 animal-days at risk)
(1) (2) (1) t (2)
Calf barn
2.39
4.23
2.80
7.58
4.54
5.45
26.66
53
Indoor
4
16,729
Outdoor
2
4,727
Combined
6
21,456
Paddocks
4
5,280
Calf unit
13
28,658
Heifer pastures
21
38,518
Dry herd
_9
3,376
115

DAILY PROBABILITY OF SEROCONVERSION TO BLV
116
.045
DAYS POSTINOCULATION
on
m
TO
O
n
O
Z
<
m
70
GO
O
z
o
03
<
Fig. VIII-1. Daily ( ) and cumulative daily ( )
probabilities for appearance of antibodies
to bovine leukemia virus (BLV) as a function
of days postinoculation with BLV. Functions
were derived from data presented by
Mammerickx et al., 1980, Van Der Maaten
and Miller, 1978a, 1978b.
CUMULATIVE PROBABILITY OF

117
k
1.0
0.0
t = 52 + k
f
t 3
Fig. VIII-2. Hypothetical proper density function showing
probabilities (Pj) of an animal becoming in¬
fected with bovine leukemia virus (BLV) in
each of three locations, j =1, 2, and 3,
prior to detection (+) of BLV infection which
followed a negative test result (-) by k
days.

CHAPTER IX
IATROGENIC TRANSMISSION OF BOVINE
LEUKEMIA VIRUS INFECTION
Introduction
It was previously suggested that vaccination pro¬
cedures contributed little, if anything, to transmission
of BLV infection in the animals studied (CHAPTER VI).
This conclusion was based on the low hazard rates of de¬
tection of BLV infection observed at ages in which vaccina¬
tions were administered. Because information on vaccina¬
tions was available, further investigation into iatrogenic
transmission of BLV infection following routine vaccinations
was warranted.
The purpose of this chapter is to test a hypothesis
that the rate of detection of BLV infection was unchanged
by vaccinations for other infectious diseases.
Materials and Methods
Infected calves were allocated to one of two groups,
depending on the date of detection of BLV infection rela¬
tive to dates of vaccinations. Calves detected within 90
days before a vaccination comprised one group, and those
detected within 90 days after a vaccination the other
group. An animal for which the 90-day intervals overlapped
118

119
was placed in the postvaccination group. Rates of detection
of BLV infection for each group were calculated as the num¬
ber of animals detected divided by the number of animal-
vaccinations. Thus, an animal was considered for each
vaccination as long as it was not detected as BLV infected
within 90 days before or after a previous vaccination.
A z statistic for the ratio of the rate-after to the
rate-before vaccination (the relative risk associated with
vaccination) was calculated as
logeRR
Z = SE(logeRR) '
where logeRR was the natural log of the relative risk,
c/c+d' w^ere a was the number detected and b the number
remaining undetected after vaccination, and c the number
detected and d the number remaining undetected prior to
vaccination, and SE(logeRR) = /1/a+l/c-l/b-l/d (Schwabe
et al., 1977). The hypothesis tested was Ho: log RR=0,
e
Ha: log RR>0.
e
Because assumptions of independence were violated by
counting an animal more than once, a second analysis was
performed which compared two independent groups. Rates of
detection of BLV infection were examined in calves 90 days
after brucellosis vaccination and in heifers 90 days before
vaccination for viral diseases. Heifers in the latter
group were the only ones vaccinated for infectious bovine
rhinotracheitis, bovine virus diarrhea, and parainfluenza-3.

120
A hypothesis that detection rates after vaccination were no
greater than before was tested using Fisher's exact test
from STATPAK of MUSIC. This test calculated the probability
of encountering frequencies as rare or rarer than those
observed.
Results
A total of 270 animal-vaccinations were conducted dur¬
ing the 27-month study. Most of these (136) were for
brucellosis (Table IX-1). Of the total vaccinated, 9
were detected within 90 days before a vaccination and 12
were detected within 90 days after a vaccination. One
heifer, detected as infected in both a pre- and post¬
vaccinal period, was assigned to the postvaccination group.
The relative risk of detection of BLV infection following
vaccination was 1.38 (Table IX-2). The calculated z
statistic was 0.74 (p=0.46). For rates of detection of
infection in the independent groups, Fisher's exact prob¬
ability was 0.33 (Table IX-3).
Discussion
The design used in examination of relative risk may
seem unorthodox because assumptions of independence were
violated. A defense of this analysis of repeated measures
rests in the supposition that an animal is equally sus¬
ceptible to BLV infection before and after vaccination.
Nevertheless, a second analysis was performed to examine

121
rates in independent groups. Fisher's exact test was used
because at least one expected cell frequency was less than
five.
The allocation of an infected heifer into a postvac¬
cinal group interjected a bias against the null hypotheses.
In spite of this maneuver, null hypotheses were accepted.
A 90-day interval was chosen for retrospective and
prospective follow-up because studies have shown that sero¬
conversion occurs within three months of natural infection
(Straub, 1978b) and within seven weeks of experimental in¬
fection (Mammerickx et al., 1980; Van Der Maaten and Miller,
1978a, 1978b).
Factors potentially confounding a vaccination effect
were present before brucellosis vaccination and after viral
vaccinations. In útero and neonatal infection may surface
after decay of colostral antibodies (Van Der Maaten et al.,
1981b). This could result in more prevaccinal detection of
infection in the brucellosis group since, by 131 days of
age, colostral antibodies were no longer detectable in 90%
of calves (CHAPTER V). Furthermore, risks of infection,
such as exposure to infected animals in paddocks or calf
pens, were not consistent before and after brucellosis
vaccination. Similarly, following viral vaccinations
heifers were inseminated and moved to the dry herd where
risk of infection increased (CHAPTER VIII). These inter¬
ventions would confound any postvaccinal effect. For these
reasons independent groups were examined only after

122
brucellosis and before virus vaccinations. Management of
heifers between these vaccinations did not appear to invoke
any confounding effect.
These results, although based on small numbers, sub¬
stantiate the interpretation of hazard rates of detection
and infection proportions discussed previously (CHAPTER VI),
as well as results of one experimental study (Roberts et al.,
1981). In that study, transmission of BLV infection could
not be demonstrated after alternately tuberculin-testing
BLV-infected cows and susceptible calves or sheep. Infec¬
tion did occur, however, when a drop of blood from a BLV-
infected animal was placed on the needle prior to inoculation.
Transmission may not have taken place in the present study
because needles used were either too small to carry an
infective dose of lymphocytes and/or withdrawal of the
needle may have wiped off infective cells.
Other plausible explanations relate to prevalence rates
of infection and passive immunity at the time of vaccina¬
tion. The chance of inoculating a susceptible animal im¬
mediately after an infected animal would be less when
prevalence rates were low. In addition, heifers vaccinated
for brucellosis may have been partially protected from BLV
infection because 10% still had detectable antibodies at
131 days of age. In one experimental study, however,
colostral antibodies failed to protect against parenteral
inoculation of BLV (Van Der Maaten et al.,
1981a).

123
Another explanation for the decline in hazard rates of
detection of infection observed during vaccination ages
could be that vaccination or use of anthelmentics instilled
a protective effect against BLV infection. Interferon has
been stimulated by Brucella abortus extracts (Keleti et al.,
1974; Kern et al., 1976) and by vaccination with infec¬
tious bovine rhinotracheitis virus (Cummins and Rosenquist,
1980) . It has been shown that interferon suppressed viral
replication of murine leukemia virus (Pitha et al., 1976)
but had no effect on visna virus (Carroll et al., 1978).
In addition, immunopotentiation has been observed in some
studies following use of the anthelmentic levamisole (Irwin,
1976; Irwin et al., 1980); however, this has not been a
consistent finding (Irwin et al., 1976).
Lymphocytotic state of donors also could-play a role
in needle transmission. The phenomenon of persistent
lymphocytosis would enhance transmission via blood because
increased numbers of BLV-infected lymphocytes become avail¬
able in peripheral blood (Kenyon, 1976; Kenyon and Piper,
1977; Kettmann et al., 1980a; Kumar et al., 1978; Paul et
al. , 1977). Persistent lymphocytosis may be age related,
with young animals less prone to develop the condition
(Hofirek et al., 1978; Levy et al., 1977; Mammerickx et al.,
1976b, 1977). This suggests that blood-borne transmission
is less likely from young donors and may explain the low
rates of detection of infection following vaccination of
young cattle in this study.

124
It has been stated that any process which transmits
blood from one animal to another probably provides a means
of transmission of BLV infection (Van Der Maaten and Miller,
1978c). Vaccination for other infectious diseases provides
a possible route of transmission through use of modified-
live virus vaccines. The viral vaccines used during the
course of this study were similar to those used in most
dairy and beef herd health programs and are modified-live
viruses derived from bovine cell lines. Contamination of
cell lines with BLV has not been reported but should be
considered until evidence proves otherwise.
Beef cattle are vaccinated routinely en masse for
various diseases, usually on an annual basis. Programs and
practices of vaccination in beef herds generally resemble
those in dairy herds. If vaccination constituted a means
of transmission, beef and dairy herds should have similar
rates of infection, as discussed previously (CHAPTER VII).
Reports of iatrogenic transmission have referred only
to procedures in which blood was sampled (Bause et al.,
1978; Maas-Inderwiesen et al., 1978; Wilesmith, 1979) or
large amounts of blood were transferred, as in premuniza-
tion (Hugoson et al., 1968; Hugoson and Brattstrom, 1980;
Marin et al., 1978; Stamatovic and Jonavic, 1968). Even
though it has been demonstrated that 2500 washed lympho¬
cytes, or 0.0005 ml of blood, are capable of infecting an
animal (Van Der Maaten and Miller, 1978b), presence of
serum neutralizing antibodies may reduce the infectivity

125
of an inoculum. In conclusion, data from this study did
not suggest transmission of BLV infection at the time of
vaccination for other infectious diseases. This may have
resulted from an insufficient infective dose carried by a
needle or from passive or nonspecific immunity protecting
an animal from a potentially infective dose. Additional
factors, such as the prevalence rate at the time of inocu¬
lation and age of donors, may further influence transmission.

Table IX-1. Summary of prevalence rates and frequency of detection of bovine leukemia
virus (BLV) infection as related to three vaccination procedures.
Vaccination
Number
vaccinated
(1)
Mean
age
(days)
Number known to be
infected with BLV
at vaccination
(2)
BLV
prevalence
rate (%)
(2) t (1)
Number detected with BLV
90 days prior
to vaccination
90 days after
vaccination
Leptospirosis
23
116
2
8.7
0
1
Brucellosis
186
131
14
7.5
8
3
IBR/BVD/PI*
61
326
8
13.1
1
8
Total
270
24
8.9
9
12
*
Infectious bovine rhinotracheitis/bovine virus diarrhea/parainfluenza-3.
126

127
Table IX-2. Frequency of detection of bovine leukemia
virus (BLV) infection before and after vac¬
cination for other infectious diseases.
Period of observation
Number of animals
Remaining un-
Detected with detected for
BLV infection BLV infection
90 days after
vaccination
12 250
90 days before
vaccination
9 261
Relative risk (RR) =
12(9+261) ,
9(12+250) 1,38 (p °*46)

Table IX-3. Frequency of detection of infection with bovine leukemia virus (BLV)
in two independent groups of animals observed before and after vac-
cinations for
other infectious
diseases.
Number
of animals
Observation period
Detected with
BLV infection
Remaining un¬
detected for
BLV infection
Total
90 days before vaccination
for viral diseases
1
52
5 3 +
90 days after vaccination
for brucellosis
6
120
126
*
Infectious bovine rhinotracheitis, bovine virus diarrhea, and parainfluenza-3.
+Fisher's exact p = 0.33.
128

CHAPTER X
SUMMARY
A prospective, longitudinal, observational design
was followed in this epidemiologic study to examine for
associations between bovine leukemia virus (BLV) infection
and host and environmental factors. In this type of
natural experiment, tests of hypotheses must be performed
within the confines of such limitations as a dichotomous
response variable, censoring, repeated measures, non¬
normality of data, and small sample sizes. Statistical
methods were applied which specifically dealt with these
analytic limitations. This methodology is applicable and
appropriate for similar epidemiologic investigations of
other infections and diseases.
Two epidemiologic tools were developed to improve
estimates of time at infection based on serologic responses.
The first was a prediction model which described the normal
limits of decay of BLV-colostral antibodies. This was
used to detect BLV infection in calves less than six
months of age. Application of this technique in control
programs for BLV infection or other infectious diseases
could reduce transmission by early detection and subsequent
removal of infected animals. The other tool developed was
a seroconversion algorithm which allocated probabilities of
129

130
infection to segments of time preceding seroconversion.
This allows examination of factors associated with infec¬
tion rather than seroconversion.
Four age-related phases of infection with BLV were
described in cattle from birth to 27 months of age. Age-
specific rates of infection were approximated by quanti¬
tative and qualitative serologic response criteria.
The first phase of BLV infection was that acquired
in útero. This was estimated to occur in 6.4% of calves
born to BLV-infected cows. In útero infection was not
associated with age or parity of the dam or with breed.
Bull calves had a higher rate of in útero infection than
heifer calves, although the difference was not significant
statistically. In útero infection was independent of the
stage of gestation in which the dam was infected. Calves
infected in útero posed no major threat of infection to
calves penned next to them in the calf barn.
The second phase of infection was observed from birth
to six months of age. Infection detected in this period
may have represented in útero infection in some calves.
Transmission did occur during this period as demonstrated
by a prevalence rate of 15% in six-month-old calves born
to noninfected cows.
Sporadic infection characterized the third phase from
6 through 16 months of age. This phase was followed by a
sharp increase in rates of infection from 16 to 27 months
of age.

131
Survival analyses of age-specific rates of detection
of BLV infection for 473 calves indicated that these rates
were independent of dam age, dam parity, dam BLV-status,
breed, or BLV-status of colostrum consumed. Interactions
were suggested for age and dam status, age and colostrum
status, and age and breed. Masking of infection by colos-
tral antibodies may explain the first two interactions,
and management differences the breed interaction.
Management practices accounted for most of the vari¬
ability in infection rates. Some types of locations oc¬
cupied by the cattle were associated with lower risks of
BLV infection. Individual outdoor calf pens and small
calf pastures were associated with lower risks of infection
relative to indoor calf pens and to the calf barn or pad-
docks, respectively. Very high risks of infection were
associated with pasturing bred heifers with dry cows.
Vaccination of calves and heifers for infectious diseases,
however, did not appear to contribute to transmission of
BLV infection.
Based on seasonal distributions of rates of BLV sero¬
conversion, no evidence was found which supported arthropod
vectors as a major mode of transmission in this population.
However, a seasonal tendency was detected for infection in
heifers over one year of age. This corresponded to move¬
ment of bred heifers into the dry herd in late winter and
spring.

132
In conclusion, transmission of BLV infection in
heifers prior to parturition could best be reduced by
limiting exposure to older infected cattle. However, seg¬
regation of calves born to BLV-infected cows does not ap¬
pear to be justified during the first two to three months
of life. Use of the prediction model for colostral anti¬
body decay can be used to identify young infected calves.
Iatrogenic and vector-borne transmission did not appear
to contribute to BLV infection in this cattle population.

Plat of the University of Florida Dairy Research
Unit; m = small pastures used as maternity areas and
as holding pens for mastitic and fresh cows; cb =
calf barn with indoor pens; op = area of outdoor calf
pens; cp = small calf pasture; cu = calf unit comprised
of 5 small pastures; p = large pastures used by heifers,
the dry herd, or lactating cows; s = small field con¬
taining sheep and goats.

plat of the
APPENDIX A
UNIVERSITY OF FLORIDA DAIRY
RESEARCH UNIT
134

APPENDIX B
AVERAGE MONTHLY HIGH AND LOW TEMPERATURES AND
RAINFALL BETWEEN JULY 1, 1979, AND SEPTEMBER 30, 1981,
FOR GAINESVILLE, FLORIDA.*
Month
Temperature
(C)
High
Low
Rainfall (cm)
January
18.91
3.91
6.32
February
20.79
6.17
10.27
March
24.73
9.99
8.27
April
29.31
13.57
6.07
May
31.28
16.70
7.51
June
34.26
21.07
11.29
July
33.97
22.48
13.51
August
33.36
21.72
8.09
September
31.99
20.84
12.40
October
28.59
15.04
1.54
November
24.12
10.79
3.49
December
20.19
6.75
8.09
*
Compiled from data received from the United States Depart¬
ment of Commerce, National Oceanographic and Atmospheric
Administration, Asheville, NC.
135

APPENDIX C
MONTHLY FREQUENCIES OF CALVES BORN ALIVE BETWEEN
JULY 1, 1979, AND JUNE 30, 1980, AT THE
UNIVERSITY OF FLORIDA DAIRY RESEARCH UNIT.
Month of birth
Number
Percent
January
36
8
February
23
5
March
11
2
April
6
1
May
7
2
June
40
9
July
45
10
August
54
12
September
68
15
October
66
15
November
50
11
December
45
10
Total
451
100
136

APPENDIX D
LOCATION SITES AT THE DAIRY RESEARCH UNIT
Fig. D-l. Cow, fitted with udder bag, due to calve in a
maternity pen.
137

138
Fig. D-2. Month-old calves in elevated pens in the calf
barn.

139
• D 3. Month-old calves in individual outdoor calf
pens.

140
Fig. D-4
Calves in paddocks adjacent to the calf barn

141
Fig. D—5. Calves 3 4 months of age on small pastures
(calf unit).

142
Fig. D-6.
Heifers grazing on large pastures.

143
MATERNITY
PASTURES
OUTSIDE PENS
INSIDE PENS
(CALF BARN)
PADDOCKS
SMALL PASTURES
(CALF UNIT)
LARGE
PASTURES
J
it
DRY COW
PASTURES
Fig. D-7. Flow chart of animal movements.

APPENDIX E
PRECIPITATION LINES OF AGAR-GEL IMMUNODIFFUSION
A = bovine leukemia virus glycoprotein-51 antigen; N =
negative control serum; 1 = antibody titer of 1:1; 4 =
antibody titer of 1:4; 8 = antibody titer of 1:8; 32 =
antibody titer of 1:32; 128 = antibody titer of 1:128;
NSL = nonspecific line.
144

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BIOGRAPHICAL SKETCH
Mark Cy Thurmond was born on February 19, 1947, in
Seattle, Washington. He graduated from high school in
Eureka, California, in 1965. From 1965 through 1972, he
attended the University of California at Davis where he
received a Bachelor of Veterinary Science degree in 1970
and a Doctor of Veterinary Medicine degree in 1972. During
high school and college he was employed as a carpenter,
mechanic, and hired ranch hand. He also raised registered
Herefords and Shorthorn heifer replacements.
After receiving the DVM, he was a private practitioner
on the northern California coast. In 1974 he returned to
the University of California at Davis where he earned a
master's degree in preventive veterinary medicine. His
research examined immunological and meteorological factors
involved in neonatal calf mortality.
From 1976 through 1977 he was a UN consultant to PAHO/
WHO in Guyana, South America. Responsibilities as a con¬
sultant included curricula establishment, teaching, and
administration in a regional Caribbean school to train
animal and public health assistants. After returning to
the U.S. in 1977, he resumed private practice in a large
dairy area in California. In 1978 he married his wife,
166

167
Audrey, a botany student in Seattle. Between 1978 and
1979 he was a research veterinarian for the University of
California. While there, he developed programs for computer
surveillance of bovine mastitis, leptospirosis prophylaxis,
and prevention of neonatal calf mortality. Since 1979, he
has been engaged in graduate studies with emphasis on
analytic epidemiology at the University of Florida.
He intends to continue teaching and research in ap¬
plied field epidemiology of food animals.

I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
Michael J. Burridge, Chairman
Associate Professor of Animal
Science and Veterinary
Medicine—IFAS
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
C&ÍCUL&&A --T. LUaC c cyC
Charles J. Wilcox f
Professor of Dairy Science
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
.o —r
Randolph I/'. Carter
Assistant Professor of
Statistics
I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
â–  v
%'â– 
: -¿¿¿i
Paul L. Nicoletti
Professor of Animal Science and
Veterinary Medicine—IFAS

I certify that I have read this study and that in my
opinion it conforms to acceptable standards of scholarly
presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.
Edward^PTjGibbs— “
Pro£eseolfof Animal Science and
Veterinary Medicine--IFAS
This dissertation was submitted to the Graduate Faculty
of the College of Agriculture and to the Graduate Council,
and was accepted as partial fulfillment of the requirements
for the degree of Doctor of Philosophy.
May 1982
.ye
/ ''i.
Dean, College of Agriculture
Dean for Graduate Studies and
Research

UNIVERSITY OF FLORIDA
3 1262 08666 9

UNIVERSITY OF FLORIDA
3 1262 08666 9