ISRAEL JOURNAL OF
VETERINARY MEDICINE
REVIEW
THE DIRECT AND INDIRECT ECONOMIC IMPACTS OF
BOVINE LEUKEMIA VIRUS INFECTION ON DAIRY
CATTLE
Vol. 60 (4) 2005 Trainin, Z.1 and Brenner, J.2
1. Israel Dairy Board, 46, HaMacabim Road, Rishon Le-Zion and
2. Kimron Veterinary Institute, P.O. Box 12, 50250 Bet Dagan, Israel
Abstract
Bovine leukemia virus (BLV) is an exogenous retrovirus and one of the most
common infectious viruses of cattle with a worldwide distribution. The bovine target
cells are mainly B-lymphocytes having the CD5 marker, however, recently it was
found that udder epithelial cells might be infected as well. BLV is the casual agent of
enzootic bovine leukemia. BLV infection is slow, life persistent and if lymphomas
appear clinically (in less than 1% of the BLV infected cows) they do so late in the
animal's life. BLV infection results in persistent lymphocytosis (PL) in about 30% of
infected cattle. The immune response of infected animals is impaired, mainly the Bcell response. This impairment is more pronounced in PL animals. The effect of this
immune disorder, on the productivity of BLV infected cattle is extensively discussed
here. Despite some inconsistencies in some of the studies, the following pathological
events can be drawn: most of the BLV infected cows exhibit a reduced economic
value that is expressed by higher susceptibility to infectious diseases, decreased
productivity, lower reproductivity and higher culling rate.
The possibility that BLV might affect humans, has been reemerged after it was
considered, for the last two decades, non-infectious to men. The findings of
antibodies to BLV proteins, which are relatively common in a high percentage of
people, also genomic sequences have been found in breast epithelial tissues derived
from women with breast cancer, should alert the cattle breeding industry into taking
precautions before hysterical public opinion might affect the industry.
The prevalence of BLV infection, in the Israeli dairy cattle is low. The mean
national infectivity rate is about 5%, and in about 60% of the tested herds no BLV
reactor was found. Therefore, if and when a BLV elimination program is introduced,
its economic burden will be rather small and will be short lasting. The improvement
in productivity and longer economic life span, which are foreseen after eradication of
BLV from the herds, will compensate for the cost of eradication in the short term.
Thus, BLV infection in cattle should not be ignored neither by the breeders and their
organizations, nor by the national authorities responsible for animal health and
welfare.
Introduction
Bovine leukemia virus (BLV) is one of the commonest infectious viruses of
cattle with a worldwide distribution, and is the primary cause of enzootic
bovine leukemia (EBL). The course of infection is slow, life persistent, and if
clinical manifestations appear they do so late in the animal's life (1,2). Much is
known about the virus (3,4) that belongs to the Retroviridae, and there is
considerable information on its mode of action, replication and induction of
transformation (5).
The aim of this review is to determine whether persistent infection of cattle
with BLV has a sufficient impact on dairy cattle that it will induce cattle
breeders to adopt preventive measures to eliminate BLV infection from their
herds.
The Virus
BLV belongs to a subfamily of exogenous retroviruses that includes the
human retroviruses HTLV-1, HTLV-2 and the simian virus, STLV-1 (4). BLV
and HTLV-1 are approximately 50% similar at the nucleotide level and share
many common features in molecular organization and disease pathogenesis.
For example, BLV and HTLV-1 are not produced in infected lymphocytes or
tumor cells in vivo, but the production of virus is induced by short-term culture
ex vivo, abnormal hematological findings occur in some but not all affected
individuals, and tumors develop in a small fraction of infected animals.
Transactivating viral gene products affect the expression of host cellular
genes and other cellular genes may influence viral expression (3, 5).
BLV infection is chronic and results in persistent B cell lymphocytosis (PL) in
20-30% of infected cattle (6). PL has long been known to have a host genetic
basis (7), which has been demonstrated to segregate within the BoLA
complex (8, 9, 10). Lymphomas occur infrequently (<1%) among BLV-infected
cattle, while high incidence herds have been identified suggesting that host
genetic factors are also involved in tumor susceptibility (7). The development
of tumors is invariably fatal, with death occurring usually within 3-6 months of
clinical detection of infection.
BLV affected cells
B-lymphocytes are the primary target cells of BLV infection, but T-cells can also be
infected although their role in pathogenesis is not known (3,11). Cows, which develop
PL as a result of BLV infection, undergo massive proliferation of B-lymphocytes that
express both Ig and CD5 antigens on their surface (12, 13).
Depelchin et al, have reported that peripheral lymphocytes from BLV-infected PL+
cows express a membrane antigen normally present on T-cells, which is characterized
as CD5 (14). They propose that the integrated BLV-proviral genome directs a cellular
gene encoding the CD5 antigen, or that BLV has a tropism for a small population of
B-cells normally expressing the CD5 antigen thus causing their clonal expansion.
Our data indicate that in contrast to BLV+PL+ cows, BLV+PL- cows represent
subpopulations (Ig+CD5-, Ig-CD5+ and CD5+Ig+) in significantly lower numbers
than BLV-negative cows (12). Here we describe a phenomenon by which BLV
infection does not necessarily transactivate CD5 genes in B-cells but can lead to a
reduction in the number of circulating CD5+ B-cells. Based on these findings, the
explanation for a transactivating effect of BLV provirus integration that encodes for
the CD5 antigen is hardly acceptable. Thus, the alternative explanation proposing that
viral tropism for a subpopulation of CD5+B-cells could be more acceptable, namely,
that BLV target cells express the CD5 cell surface antigen. On one hand, viral
integration may cause proliferation of this population leading to PL, while on the
other hand it suppresses the proliferation of these cells. Recently it was suggested that
the mode of action of BLV on B-CD5+ cells, is to block their apoptosis, rather than to
trigger their proliferation (15).
The immunological response to BLV infection
The identification of BLV epitopes that serve as targets for humoral and cellular
immune responses has been extensively investigated (16, 17), while the natural
history of BLV infection and the structural features of the virus have been extensively
documented. Antibodies to several viral proteins can be detected within days or weeks
after experimental infection with BLV (3). Antibodies to some proteins (e.g. gp51env)
usually persist for the lifetime of the infected animal, whereas others, such as anti-rex,
may fluctuate cyclically (18). The role of these antibodies in limiting the early spread
of BLV infection after natural experimental exposure has not been determined.
Detailed studies have identified immunodominant peptides for antibodies to the BLV
env protein (19); 8 unique and three cross-reactive epitopes on BLV-gp51 env were
identified using mouse monoclonal antibodies. Three conformational epitopes were
shown to be responsible for syncytium induction and infectivity. Six sequential
epitopes were also identified and mapped towards the OH- terminus of BLV-gp env
protein. Immunodominant peptides of the other encoded proteins have not been
identified, although all the BLV proteins are apparently immunogenic (3, 18).
Immune impairment
Like other retroviruses, infection with BLV results in deregulation of the host's
immune system at both humoral and cellular levels.
We observed more than 3 decades ago, a reduction in IgM-producing cells in the
spleen and lymph nodes of EBL-affected cows by immunofluorescence (20) and
confirmed findings on the absence of serum IgM of leukotic cattle at the terminal
stages of the disease (21).
Further studies indicated that the primary response of leukemic cattle is impaired, and
this impairment is expressed mainly by a lower than normal production of
biologically active IgM antibodies (22). Moreover, we found that serum Ig levels do
not necessarily reflect the immunocompetence of these animals. It might be assumed
that the serum Igs of leukemic cattle is not necessarily specific antibodies, and this
might express a defective mechanism of Ig production (23).
The response of experimentally BLV-infected cattle to priming with a synthetic
antigen (T,G)-A-L was found to be greatly diminished as compared to healthy
controls (24). Thus it seems that the immune response in BLV-infected cows could be
either depressed, or being triggered by an antigenic stimulus, finds expression in the
production of incomplete molecules.
Direct economic loss of BLV infection
Because BLV infection affects the immune system of cattle its impact on herd health
and economy could be more extensive than direct loss from death following
lymphomas. This can be learned from studies on the susceptibility of BLV-infected
cows to infectious diseases and the rates of production, reproduction and culling.
The economic impact of death following lymphomas
The most pronounced clinical manifestation of BLV infection is the appearance of
lymphomas with 100% mortality. Death occurs usually within 2 to 6 mo postdiagnosis. The occurrence of lymphomas, previously known as lymphosarcoma, used
to be 1 to 3% of BLV-infected cows, yet with the recent tendency, to an increase the
turnover of dairy cattle in a herd, with a turnover decrease life span, this percentage is
reduced. Nevertheless, a USA study carried out by Plezer estimated that lymphoma
cases cost the US dairy industry more than 16 million $ annually (25). This includes
direct costs resulting from loss of diseased cows. The costs of veterinary services,
medications and time span until the right diagnosis is determined, may be much
higher. Moreover, these costs do not include those resulting from the ban on
exportation of lifestock as well as semen and embryos from affected herds to most
countries worldwide.
Susceptibility to infectious diseases
The detrimental effect of BLV infection on the bovine immune system may cause a
higher susceptibility to opportunistic and infectious agents resulting in clinical
diseases. The diseases examined in this content include mastitis, metritis, lameness
diseases and ringworm (Trichophyton verrucosum) infection (Table 1a,2).
Of the 5 publications in which the connection of BLV infection with clinical or subclinical disease of mastitis were examined, 3 were performed on one herd employing
3 or 4 years of retrospective study. Reinhardt et al (26), tested cows above 60 mo old,
and found cases of mastitis in 80% (12 out of 15) of BLV-positive vs. 57% BLVnegative cows (15 out of 26). In another work, Huber et al (27) found that the relative
risk of clinical mastitis in BLV antibody-positive cows was 1.3 in a study carried out
over 4 successive years in one herd. Both results showed less mastitis occurring in
BLV-negative cows, but were not statistically significant. Sandev et al (28) carried
out studies on 26 cows divided into 3 groups on the basis of serological and
hematological analyses for bovine leucosis: group I- BLV+PL-, group II- BLV+PL+,
and group III - BLV-PL-. A statistically significant difference was observed in the
incidence of sub-clinical mastitis in cows from group II - (BLV+PL+ 77% compared
with BLV-negative cows (25%) (P<0.05). The incidence of sub-clinical mastitis of
BLV+PL- cows in this study was 44%. The most commonly isolated bacteria were
Streptococcus agalactiae (47%) followed by Staphylococcus spp (36%).
Two additional large-scale studies were carried out; one described by Jacobs et al.,
(29) was carried out on 61 herds. Although somatic cell count as an indication of subclinical mastitis, was related significantly to BLV status using simple tests of
association, once the variables of herd size, age and days in milk were controlled,
these differences were removed. In another study where 14425 herds were included,
Emanuelson et al showed a tendency towards a higher incidence of mastitis among
BLV-infected than in BLV-free herds, as was also reflected in the bulk-milk somatic
cell count (30).
In summary, five of the 6 studies described a higher incidence of mastitis among
BLV-infected cows and BLV-infected herds than in BLV-free cows and free herds;
three studies did not show that this difference was statistically significant, while two
studies showed a significant difference.
Jacobs et al could not find a significant relationship between BLV infectivity and
metritis (29).
Brenner et al have described the association between ringworm and BLV infection
(31), in which 66 cattle were naturally infected with Trichophyton verrucosum. Fiftythree recovered spontaneously up to 4 mo post-infection (Table 2). The BLV test
revealed 32 positive reactors. Twelve out of the 13 animals still affected with
ringworm were BLV-positive, while only one was BLV seronegative. Of the 34 BLVnegative animals, 33 (97%) recovered spontaneously from ringworm, in contrast to 20
of the 32 (62%) BLV-positive cows. A higher rate of spontaneous recovery from
ringworm was found of the BLV-negative cows compared with the positive group
(P<0.0005).
Emanuelson et al examined the relationship between the herd level of BLV infection
and disease incidence in 14424 herds (32), and showed a significant association for
infectious diseases with BLV infectivity, for example gastro/bronco tracts and hoof
problems. In contrast, non-infectious diseases such as paresis, ketosis, and leg
problems were not associated.
BLV infection and milk production
Does BLV infection affect milk production in dairy cattle? The results of number of
investigations are summarized in Table 1b.
Brenner et al compared milk productivity rate between 102 BLV-positive cows and
their age-matched BLV-negative counterparts (31). The BVL-negative cows produced
1123kg (3.5%) more milk than their BLV-reactors counterparts. This difference was
not significant (P>0.05). However, when the same test was applied to compare only
the last milking period rather then the entire milk yield, the outcome become
significant with a mean difference of 7.4%.
Reinhardt et al, in retrospective studies over 3 years in one herd, found that BLV
positive cows produced 156 kg milk less than the BLV negative cows corrected to
3.5% in 305 days lactation (26).
Emanuelson et al conducted a study including 14425 herds, comparing milk
productivity in BLV-infected herds (at least one animal was BLV-positive) to BLVfree herds. They found that milk production was reduced by about 2.5% in herds
classified as BLV-infected compared with BLV-free. These differences were
statistically highly significant (30).
On the other hand, Jacobs et al (29), analyzing 2079 cows from 61 herds, could not
find significant differences in milk production between BLV-positive and BLVnegative cows. Although by simple statistical tests, reduced milk production was
related significantly to BLV reactors, further analysis failed to show an association
between milk production and BLV positivity. Further studies made by this group on
998 cows from 268 dairy herds reached to the same conclusion, namely, no
significant association were detected between BLV serpositivity and milk production
(39).
In another report Langson et al (32) found that positive cows tended to produce more
milk and to produce at a higher rate for the first 2 lactations. For subsequent
lactations, the negative cows had a higher production although the differences were
not statistically significant.
Pollari et al distinguished PL-positive from PL-negative BLV-infected cows in a
highly infected herd of 400 dairy cows (33), and found that BLV-infected cows
yielded more milk on average than uninfected cows. Only cows with lymphocytosis
(PL+) had reduced milk production relative to seronegative cows, although this
difference was not significant.
In another study performed on 547 Holstein dairy cows, the mean daily milk yield
was 11% lower in BLV+ than in BLV- cattle (19.4 vs. 21.8 kg, respectively), and this
was significant (34). In a stringent multivariate analysis performed on 1330 cows
from 102 dairy herds, Sargeant et al found a negative association between herd-level
milk production and BLV status (35). Recently, a large-scale study was performed to
investigate the association between BLV infection and annual value of production on
dairy herds in the United States (36); 1006 herds in 20 states, with at least 30 dairy
cows per herd were tested. A multivariate regression model was used with the 976
herds presenting complete data for analysis. When compared with herds with no testpositive cows, herds with test-positive cows yielded 218 kg (3%) less milk calculated
in US$, for the entire dairy industry in the USA, BLV seropositivity was associated
with a loss to producers of $285 million and $240 million for consumers. Most of this,
$525 million, industry loss, was due to reduced milk production in BLV-positive
herds (36).
Five studies were devoted to the question whether an association between milk fat
level and BLV status existed (Table 1c). One study in which no significant decrease
in milk production was shown, found no decrease in fat level either (37). In another
study (33) in which PL+ cows showed reduced milk production before culling, a
similar reduction was found in their fat levels. In two studies, investigators could not
find any difference between BLV+ and BLV- in fat production, although they showed
a difference in milk productivity (31, 36). Two studies found reduced fat production
in BLV-infected dairy cattle with an increased significance in PL+ cows (38, 58).
BLV infection and reproduction
The question investigated by several groups to what extent does BLV infection affect
the reproduction rate was here documented in 5 reports (Table 1 d).
Reinhardt et al analyzing retrospectively over 3 years 220 cows of which a third were
BLV positive and concluded that the fertility of the positive animals was not affected
(26). Langston et al reached a similar conclusion after examining the lengths of
calving intervals and non-lactating period (32). D'Angelino et al tested 444 Holstein
dairy cows for calving intervals, and found a mean value of 474 days for the BLVpositive cows and 455 (19 days less) for the negative ones (34); this difference was
not statistically significant. A comparison of retrospective rates was carried by
Brenner et al on 103 BLV-positive and 103-BLV-negative counterpart cows (31). The
total mean of calving intervals was 357.3 days for a cow belonging to the BLVnegative group while for her BLV-positive counterpart it was 405.2days. The mean
difference of 47.9 days open between the groups was insignificant at the 5% level.
However, Heald et al (39) who analyzed 998 cows from 268 dairy herds, and failed to
find any difference in milk production, had shown that BLV positive cows had a
slight statistically significant increase in calving interval. Two reports that examined
the number of inseminations failed to find any differences between BLV positive and
negative cows (26, 27).
BLV infection and economic-productive life span
One of the parameters by which the economic impact of BLV infection on dairy cows
can be evaluated is their culling rate. This parameter was evaluated either by
comparing individual infected and uninfected cows (27, 31, 33, 39, 40-42) on a herd
basis or comparing infected and uninfected herds (30, 36) (Table 1e). Huber et al
studied a Holstein herd starting with 145 cows over 4 consecutive years, and failed to
find significant differences in the proportions of BLV negative and positive cows
remaining in the herd each year (27), while Heald et al reached the same conclusion
from testing 998 cows from 268 dairy herds (39). In contrast, Thurmond et al came to
the opposite conclusion after testing 200 dairy cows in one herd (40), when they
found that the culling rates increased with age and were significantly greater in
seropositive than in seronegative cows (P=0.049). The survival analysis of cows from
3.5 years and older, showed significantly longer survival among BLV-negative cows
than among positive cows (P=0.008).
We have studied a group of 983 cows that were included in a trial conducted to find
out the difference in survival rates between BLV-positive cows and the entire cow
population (31). During the period of observation (3 yrs), 132 positive reactors were
found, and 51 (38.64%) were culled. In the same period, 91 out of 851 seronegative
cows (10.69%) were disposed of; this difference was found to be highly significant
(Table 3).
In a later study 98 cow-pairs were included in the trial designed to determine the
difference in the survival rates of BLV-positive cows and their BLV-free, agematched counterparts; 67 positive cows were culled before their BLV-negative
counterparts, whereas ge-matched ones. This difference in culling rate was found to
be highly significant (P< 0.01) (31).
Pollari et al (41) tested one herd of 1078 cows over 24 mo and concluded that the risk
of being culled increased with age for seropositive but not for seronegative cows.
Infected cows had a higher cull rate than non-infected cows in animals older than 3
years. The cull rate was lower for infected cows than for uninfected cows at younger
ages, but this difference was not statistically significant at the 5% level. When these
same survey compared cull rates between seropositive, non-lymphocytic cows and
lymphocytic ones they found that the later were culled 4mo. younger on average than
non-lymphocytic, seropositive cows (33). In a recent study Rhodes et al analyzed 593
cows in one dairy herd but did not find significant difference in the cull rate between
seropositive and seronegative cattle (42).
Two reports have compared the cull rate between BLV-infected and BLV-free herds.
Emanuelson et al analyzing 14424 herds and showed a higher odds ratio for culling in
BLV-infected vs. BLV-free herds (32), whereas Ott et al found a negative association
between group culling and BLV prevalence (36). The later however, described a
positive association between a significant reduction in milk production and BLV
prevalence.
The indirect impact of BLV infection prevalence on the dairy industry
The question whether BLV can act as a zoonotic agent, i.e., transmitted to humans
will be considered briefly.
In principle, retroviruses are regarded as species specific that do not cross the species
barrier and until recently BLV was being regarded as such. In the 1970s, intense
efforts were made to determine whether humans might be infected through
consumption of dairy products or from occupational exposure to cattle.
Several serological surveys failed to detect human antibodies to BLV envelope
glycoprotein (gp51) and/or capsid protein (p24) (43-46). Based on these studies the
prevalent opinion for two decades has been that BLV is not transmissible to humans
and no human disease has ever been attributed to BLV (47). These carefully
performed studies used mainly the agar-gel-immuno-diffusion (AGID) techniques that
were the state-of-the-art at that time. In the past decade it appears that some cattle
testing negative for anti-BLV antibodies by AGID are actually positive by
immunoblotting or enzyme-linked immunosorbent assay (ELISA) (48-50). Recently,
Buerhing et al conducted a study in which 257 human sera were tested by
immunoblotting (51). They found that 74% of the sera tested were positive to BLV
capsid antigen (p24). The specificity of the reactivity was demonstrated by
competition studies and by eliminating cross-reacting antibodies to other chronic
human viruses, among them two human retroviruses, human T leukemia virus 1
(HTLV 1) and the human immunodeficiency virus (HIV). These authors suggest that
the main route of possible BLV transmission from cow to man is probably through
milk consumption. It was shown that calves can be BLV-infected through milk from
infected cows. It is also known that breast milk of the closely related HTLV1, is the
main source of infectivity to infants up to at least 1 year of age (52, 53). In addition,
Buehring et al had conducted a survey to determine whether humans were infected
with BLV and whether it might play a role in breast cancer (54). They employed
immunohistochemistry and in situ PCR to detect viral proteins and proviral DNA,
respectively, as signs of infection in surgically excised human breast tissues. Most of
the breast tissues had evidence of a BLV proviral genome and 4 out of 27 were
positive for capsid protein.
Brief description of the current epidemiological status of BLV in Israel
The prevalence of BLV reactors in Israel to date to 2005, is presented in Table 4. The
total number of tested adult cows was 12211 representing 172 settlements; where 126
farms were large cooperative (with more than 250 lactating cows) farms and the
remaining 46 settlements comprised 152 small holder-type dairy herds (with less than
250 lactating cows).
The total average number of BLV reactors found in this work was 5% with ± standard
error deviation of 15%. The 3.5% prevalence mean of BLV-reactors found in the
large cooperatives was much lower statistically that the 7.2% prevalence rate found in
the small-holder type farms.
In addition, Figure 1 depicts the 10% percentile prevalence of BLV-gp51 reactors in
each type of dairy herd. The percentage of farms with no BLV reactors was
approximately the same, namely, over 60% of the farms of large and small herds, had
no BLV-reactor. The relatively higher rise of BLV reactor prevalence in the
remaining 10%-percentiles in the small type dairy herds, could be partially explained
by the relative small number of cow samples taken from the small-type dairy herds
compared with the larger number of samples taken from the large type farms. Thus,
each individual positive sample weighted more if a small sample size was tested. The
higher prevalence of BLV reactors in the small holders is probably a result of
different management regarding the segregation of animals according to age applied
in both farm types. In the small farms the young stock, including sometimes the
yearling heifers, are kept in the yard containing adult milking cows, where a higher
number of BLV reactors is present (55), due to reduced space available in this type of
farm compared with to the relatively vast area of sheds available in the large
cooperative dairy farms.
Discussion
When a program is initiated to control or eradicate a disease in the dairy industry, its
economics should be analyzed with respect to the costs and the benefits of the
program. If it involves a zoonotic disease the initiation of control measures goes
beyond the direct costs and benefits criteria, since they are influenced mostly by its
potential hazard to human.
BLV is one of the most common viral agents affecting cattle with a worldwide
distribution. There are countries (mostly European) that initiated programs to
eradicate BLV infection. Others like the USA, Canada and Israel did not. No surprise,
therefore that most of the published works on the economic impact of BLV infection
originate from these countries.
In the present review we have presented the most recent data on BLV, evaluating
mainly the loss of production, reproduction and occurrence of secondary infectious
diseases in sub-clinically affected animals. These might be relevant to the economic
survival rate of infected cattle.
Once BLV infection becomes established chronically in a herd, the incidence of
clinical manifestations of lymphomas is below 1% and can be regarded as a
negligible; thus this will not stimulate breeders to initiate an elimination program in
their herds.
As was shown, BLV infection of cows may cause impairment of the immune system
mainly in the B-cells immune response (56). It is therefore reasonable to expect that
prolonged infection may increase the susceptibility of BLV-infected cows to
secondary infectious agents, especially bacteria, which cause clinical or sub-clinical
infectious diseases, and might find its expression in decreased productivity, eventually
decreased reproductivity, and a shorter economic life span. Hence the majority of the
manuscripts evaluating these criteria found an association between BLV infection and
decreased economic values of infected cows or herds. In contrast, there are reports
that failed to find such an association. On the surface, this discrepancy is seemingly
hard to understand. Nevertheless, an explanation is offered here for those sometimescontradictory results by analyzing the use of the experimental animal population.
It is well established that retroviruses that are known to cause severe
immnunodeficiency, do so after a prolonged latent period (57). Due to the length of
the interval between tests in cross-herd examinations, the exact time of infection
cannot be determined accurately. It is plausible that during the period immediately
following infection, the immune response of an infected cow remains unchanged or
only slightly diminished. Yet, its condition will deteriorate with time.
We have shown previously that due to management policy in BLV infected herds, the
percentage of infected calves is very low, and cows are massively infected only
during their second lactation period in large cooperative herds, i.e., not before they
reach the age of 2.5-3 years (31). Furthermore, Wu et al (38) demonstrated that
genetic merits are correlated with susceptibility to BLV infection and also PL. Cows
that are genetically high milk producers are more susceptible to BLV infection and
become PL (10, 38, 58).
In view of these data, we propose that a follow up study should be performed in
which time of infection is recorded, and which groupings are made by age or lactation
number in order to present relevant and conclusive data. As mentioned above, in most
cases, the time of infection is unknown. This hurdle can be overcome by using very
large scale investigations on herd levels as performed by Emauelson et al (30), and
Ott et al (36) or by testing a large herd in which enough higher aged individuals are
available as done by Thurmond et al (40). Another possibility is to perform a pairs
study, BLV+ vs. BLV- cow, according to the following criteria: (a) both members of
pair were born, raised and kept in the same herd, (b) the interval between the dates of
birth of each member of the pair did not exceed 30 days, and (c) complete records
were available of milk and breeding performance over the entire lifespan of each
animal, as was carried out by Brenner et al (31).
Furthermore, most reports did not distinguish between PL+ and PL- in the positive
cows. No doubt the immune system of PL+ cows is more severely affected than PLones, and thus they could be more vulnerable to clinical or sub-clinical disorders. Da
et al (58) who distinguished between PL+ and PL- seropositive cows found that the
relationship between PL and milk production traits was most pronounced after cows
had PL for 2 years. For the first two lactations prior to development of PL, these cows
had similar milk and fat yields, as did other cows of the same age. After one year with
PL, cows that remained in the herd experienced a precipitous and significant drop in
milk yield than did herd-mates of the same age. Discussing the negative results
obtained by others, Da et al (58) indicated that the essential problem in interpretation
or comparing these studies is that "seropositive" animals are heterogeneous for
disease status. For example, antibodies to BLV can be found in animals recently
exposed to BLV but are asymptomatic, in animals with PL (above 3 years old) and in
animals with tumors (usually above 6 years). Furthermore, the genetic potential for
milk production was not taken into account in these early studies. Thus, inconsistent
results between these early studies are not surprising. Da et al (58) approach for
analyzing the effect of BLV infection on milk production was to subdivide the
seropositive animals into PL+ and non-PL categories and to account for the potential
of various measures of milk production for each animal. This approach resulted in a
clear picture of the effect of sub-clinical BLV infection on milk production.
It is not surprising that Langston et al (32) found when BLV+ and BLV- cows were
compared that positive cows tended to produce more milk for the first 2 lactations
while for subsequent lactations the BLV negative cows had higher milk production.
Ott et al (36) found a mean decline in milk production among test-positive herds of
218 kg per cow (2.7%) less than did test-negative BLV herds. This result is similar to
that of Emunaelson et al (30) who analyzed 14424 herds in Sweden and found that
BLV-infected herds produced 2.5% less milk than BLV-free herd. Converting these
data to the cow level, Ott et al (36) found a 470 Kg loss per positive cow (5.7%). This
is more than the data presented by Brenner et al (31) and Reinhardt (26) and Sergeant
et al (35) that found 3.0-3.5% lower production by seropositive cows, but is less than
the 11% decline reported by D'Angelino et al (34). Indeed, our data revealed that
while the mean difference of milk production was only 3.5% calculated for the whole
productive lifespan, it increased to 7.5% in the last milking period (31).
The most obvious explanation for the reduced productivity of BLV-positive cows,
especially those which develop PL, is increased susceptibility to infectious agents. In
5 out of 6 works, which found an association between clinical or sub-clinical mastitis
and BLV positivity, we could find support for this hypothesis (26-28, 30, 36).
However, Motlon and Buehirng (59) have suggested a different explanation for this
phenomenon. They found that mammary epithelial cells could be infected by BLV
(60). This finding raises the possibility that the virus could affect milk production
directly at the cellular level. The most telling result of this work (61) was the effect of
BLV on casein production. The epithelial transfected cells with BLV could not
produce significant amount of casein, and this inhibition was determined to be at the
transcription level (59). It has to be mentioned that these results were obtained in
vitro, and it has to be clarified whether this also occurs in vivo.
The association of BLV infection and infectious diseases, other than mastitis, was
determined significantly by Brenner et al (31), who showed the correlation between
BLV-infection and lack of spontaneous recovery from Trichophyton verrucosum
infection.
Emanuelson et al (30) showed by comparing BLV-infected vs. non-infected herds,
that BLV-infected herds ran a higher risk of disease of a possible infectious etiology
(mastitis, gastro/bronco tracts and hoof problem), while non-infectious diseases did
not occur.
It should be mentioned that no specific infectious agent associated with BLV infection
was found.
According the reports presented in this review, the effect of BLV infection on bovine
reproductivity seems to be minor. The only effect was on the calving interval, which
was found significant by some (30, 36) and insignificant by other gruops (31, 34, 35).
If BLV infection affects the immune system of a cow to such an extent that it ceases
to be productive enough to be kept in the herd, this could result on increased culling
rate. Indeed, the majority of the works analyzing the cull rate could find a significant
increase in cull rate for BLV-positive cows above 3 years of age (30, 31, 40, 41) and
more so for PL+ cows (33). The one exception is the work of Ott et al (36) who found
a negative association between culling rate and BLV prevalence when comparing
positive with negative herds. The same group found a significant decrease in milk
production associated with BLV prevalence. They suggested that the negative
association between culling rate and BLV prevalence could be partially explained by
the association between seropositivity and the change in milk cow inventory. In
general, herds with BLV positive cows were expanding their cow numbers faster than
herds without BLV positive cows. With a positive relationship between increasing
cow numbers and BLV positivity, it was not surprising to find that the culling rate
proportions in positive herds were less than those in negative herds (36).
Nevertheless, it seems that in herds that replace or expand their cow numbers from
their own stock of replacement heifers, the culling rate is strongly associated with
BLV infectivity.
In accordance with the submitted data and the conclusion drawn in the discussion, we
suggest the following pathogenicity.
Most cows are exposed to BLV infection when they join the herd of lactating adult
cows. In small herds it may occur in the first lactation, and mostly during the second
lactation in the large herds. A cow that possesses genes for high productivity is more
likely to contract BLV infection than genetically low producer cows, and it tends to
develop PL. Although infection with BLV may by infecting udder tissue reduce
productivity, it is more logical that drawback of the well-being of the BLV infected
cow results from the detrimental effect on the immune state of the animal, and more
so in PL+ cows. This immune impairment causes increased susceptibility to infectious
diseases mostly in sub-clinical terms, which leads to decreased milk production and
slight decreased reproductivity. This finds its expression in a higher culling rate in the
herd.
These events develop rather slowly, thus only cows 3-4 years of age and older
deteriorate in profitability. Thus the impact of BLV infectivity on herds in which the
management policy is to undertake short-term replacement of the lactation cows after
the third or forth lactation, regardless of their economical value, is rather small and
might be even negligible. However, in herds where culling criteria are based on
individual achievements, there is segregation between high and low productive cows,
and the impact of BLV infection might be very significant. Owners of these herds will
very probably benefit economically from the attempt to control and eliminate the
BLV infection from their herds.
The even slight possibility that BLV might infect humans illuminates the impact of
BLV infection of dairy herds from a different point of view. The recent report of
Buehring et al where a significant proportion of people had antibodies to BLV (51),
who may have been exposed by consumption of beef and dairy products, should alert
the beef and dairy cattle industry. The existence of BLV antibodies in humans blood
does not necessarily imply that positive individuals are infected by BLV. The
antibodies can result from denatured BLV proteins in pasteurized milk products.
Nevertheless Buehrings group found that udder epithelial cells, along with Blymphocytes (60), can be infected by BLV, and furthermore, BLV can transfect those
cells (59). In a subsequent study Boehring et al found BLV viral sequences in breast
tissue of women with breast cancer (60).
If additional studies by this group and others will approve and further strengthen these
findings, the banning of all animal products from BLV-infected herds will be very
imminent. Indeed, this work has evoked a reaction in the electronic media addressed
to the public under the title "Have millions of Americans been infected with a cow
cancer virus?" (61).
We present here data showing that the prevalence of BLV infectivity among Israeli
dairy cattle is rather low 3.5% in the large herds and 7.2% in the small herds.
Furthermore, approximately 60% of all herds in Israel seem to be free from BLV
infection.
Whether the situation is favorable as a starting point for a campaign for the control, or
even eradication, of BLV infection, is not within the scope of this review. However,
we think that as long as the majority of Israeli herds seems to be clean or have a
relatively low prevalence of BLV reactors (less than 5%), might be a favorable
background for adopting either the test and isolate, or test and slaughter (55), or the
test and corrective management (62) approaches in order to reduce BLV incidence in
Israel.
In conclusion we are convinced that BLV infection in cattle cannot and should not be
ignored by the breeders and their organizations, nor by the national authorities, who
are responsible for animal health and for public health.
LINKS TO OTHER ARTICLES IN THIS ISSUE
References
1. bovine leucosis. In: A. Burny, and M. Mammerickx, (eds), Enzootic bovine leucosis and
bovine leukemia. Martinus Nijhoff Publishing, Boston, USA. 1987.
2. Swartz, I. and Levi, D. Pathobiology of bovine leukemia virus. Vet. Res. 25:521-536. 1994.
3. Burny, A., Bruck, C., Chantrenne, H., Cleuter, Y., Dekegel, D., Kettmann, R, Lecercq, M.,
Leunen, J., Mammerickx, M., and Porteetelle, D. Bovine leukemia virus: molecular biology
and epidemiology. In: G Klein (eds) Viral Oncology. Raven Press, New York, p 231-289.
1980.
4. Sagata, N., Yasunaga,T., Tsuzuku-Kawamura, J., Ogawa, Y. and Ikawa, Y. Complete
nucleotide sequence of the genome of bovine leukemia virus: its evolutionary relationship to
other retroviruses. Proc. Natl. Acad. Sci., 25: 677-681. 1985.
5. Rosen, C.A., Sodroski, J.G., Kettaman, R., Burny, A. and Haseltine, R.A. Trans activation
of the bovine leukemia virus long terminal repeat in BLC-infected cells. Science, 227:320-322.
1985.
6. Miller, J.M. and Van der Maaten, M.J. Infectivity tests of secretions and execrations from
cattle infected with bovine leukemia virus. J. Natl. Cancer Inst. 52:425-428. 1979.
7. Croshaw, J.E. Jr., Abt D. A., Marshak, R.R., Hare, W.C.D. and Switzer, J. Pedigree studies
in bovine lymphosarcoma. Ann N.Y. Acad, Sci., 10: 1193-11202. 1963.
8. Levin, H.A. Disease resistant and immune response genes in cattle: Strategies for their
detection and evidence of their existence. J. Dairy Sci. 72: 1334-1348. 1989.
9. Xu, A., Van, Eijk, M.J.T. Park, C. and Lewin, H.A. Polymorphism in BoLa-DRB3 exon-2
correlates with resistance to persistent lymphocytosis caused by bovine leukemia virus. J.
Immunol. 151: 6977-6985. 1993.
10. Van Eijk, M.J. T., Stewart, J.A., Beever, J.E. Fernando, R.L. and Lewin, H.A.
Development of persistent lymphocytosis in cattle is closely associated with DRB2.
Immunogenetics, 37: 64-68. 1992
11. Stott, M.L., Thurmond, M.C., and Dunn, S.J.,Osburn, B.I. and Stott, J.L. Integrated bovine
leucosis proviral DNA in T helper and T cytotoxic/ suppressor lymphocytes. J. Gen. Virol. 72:
307. 1991.
12. Meirom, R., Brenner, J. and Trainin, Z. BLV infected lymphocytes exhibit two patterns of
expression as determined by Ig and CD5 markers. Vet. Immunol. Immunopathol. 36: 179186.1993.
13. Meirom, R., Moss, S. and Brenner, J. Bovine leukemia virus-gp51 antigen expression is
associated with CD5 and IG markers on the infected lymphocytes. Vet. Immunol.
Immunopathol. 59: 113-119. 1997.
14. Depelchin, A., Letesson, J.J., Lostrie-Trussart, N., Mammerickx, M. and Burny, A. Bovine
leukemia virus (BLV)-infected cells express a marker similar to the CD5 T cell marker.
Immunol. Lett. 20: 69-76. 1989.
15. Cantor, G.H., Pritchard, S.M., Dequiedt, F., Willems, L., Kettamann, R. and Davisd, W.C.
CD5 is dissociated from the B-Cell receptor in B cell from bovine leukemia virus-infected
persistently lymphocytotic cattle: consequences to B-cell receptor mediated apoptosis. J.
Virol. 75: 1689-1696. 2001.
16. Cornil, I., Deplon, P., Parodi, A.L. and Levi, D. T-B cooperation for bovine leukemia virus
expression in ovine lymphocytes. Leukemia. 2:313-317. 1988.
17. Mager, A., Masengo, R., Mammerickx, M. and Letesson, J.J. T-cell proliferative response
to BLV; identification of T cell epitopes on the major core protein (p24) in BLV-infected- cattle
with normal haematological values. J. Gen. Virol. 75: 2223-2231. 1994.
18. Powers, M.A., Grossman, D., Kidd, L. C. and Radke, K. Episodic occurrence of antibodies
against the bovine leukemia virus rex protein during the course of infection in sheep. J. Virol.
65: 4959-4965. 1991.
19. Callebaut, I., Burny, A., Krchnak V., Gras-Masse, Wathelet, B. and Portetelle, D. Use of
synthetic peptides to map sequential recognized by monoclonal antibodies on the bovine
leukemia external glycoprotein. Virology, 185: 48-55. 1991.
20. Trainin, Z. and Klopfer, U. Immunofluorescent studies of lymph nodes and spleen of
leukotic cattle for production of IgM and IgG. Cancer Res. 71: 1968-1970. 1971.
21. Trainin, Z., Nobel. T. A., Klopfer, U. and Neumann, F. Absence of Macroglobulin (IgM) in
the sera of leukotic cattle and diagnosis of bovine leucosis. Refuah Vet. 25: 185.1968.
22. Trainin, Z., Ungar-Waron, H., Meirom, R., Barnea, A. and Sela M. IgG and IgM antibodies
in normal and leukaemic cattle. J. Comp. Pathol. 86: 571: 580. 1976.
23. Ungar-Waron, H., Glucknan, A., Brenner, J. and Trainin, Z. Use of synthetic antigen to
predetermine the responsiveness of cattle to vaccine induced immunity. Vaccine: 2:136-139.
1984.
24. Ungar-Waron, H., Avraham, R., Glucknan, A. and Trainin, Z. Reduced
immunocompetence of antibodies in leukemic cattle. Ann Rech. Vet. 9: 815-819. 1978.
25. Pelzer, K.D. Economics of bovine leukemia virus infection. Vet Clin. North Am. Food
Anim. Proct. 13: 129-141. 1997.
26. Reinhardt, G., Hochstein-Mintzel, V., Riedemann, S., Leal, H. and Niedda, M. Estudio
serologico de leucosis enzootica bovina en un predia de la provencia da Valdivia y su relation
a parametros productivos y reproductivos. J. Ved. Med. B, 35: 178-185. 1988.
27. Huber, N. L., DiGiacomo, R.F., Evermann, J.F. and Studer, E. Bovine leukemia virus
infection in a large Holstein herd: Prospective comparison of production and reproductive
performance in antibody-negative and antibody-positive cows. Am. J. Vet. Res. 42: 14771481. 1981.
28. Sandev, N., Koleva, M., Binev, R. and Ilieva, D. Influence of enzootic bovine leucosis
upon the incidence of subclinical mastitis in cows at a different stage of infection. Vet. Arch.
74: 411-416. 2004.
29. Jacobs, R. M., Heeney, J. L., Godkin, M. A., Leslie, K. E., Taylor, J. A., Davies, C. and
Valli, E. O. Production and related variables in bovine leukemia virus-infected cows. Vet. Res.
Comm. 15: 463-474. 1991.
30. Emanuelson, U., Scherling, K. and Pettersson, H. Relationship between herd bovine
leukemia virus infection status and reproduction, disease incidence, and productivity in
Swedish dairy herds. Prev. Vet. Med. 12: 121-31. 1992.
31. Brenner, J., Van-Haam, M., Savir, D. and Trainin, Z. The implication of BLV-infection in
the production, reproductive capacity and survival rate of a dairy cow. Vet. Immunol.
Immunopathol. 22: 299-305. 1989.
www.aphis.usda.gov/vs/ceah/cahm/Dairy_cattle/96blv.htm
48. Walker, P. J. Molloy, J. B. and Rodwell, B. J. A protein immunoblot test for detection of
bovine leukemia virus p24 antibody in cattle and experimentally infected sheep. J. Virol.
Methods. 15: 201-211. 1987.
49. Have P. and Hoff-Jorgensen, R. Demonstrating of antibodies against bovine leukemia
virus (BLV) by blocking ELISA using bovine polyclonal anti-BLV immunoglobulin. Vet.
Microbiol. 27: 221-229. 1991.
50. Grover, Y. P. and Guillemain, B. An immunoblotting procedure for detection of antibodies
against bovine leukemia virus in cattle. J. Vet. Med. B. 39: 48-52. 1992.
51. Buehring, G. C. Philpott, S. M. and Choi, K. Y. Humans have antibodies reactive with
bovine leukemia virus. Aids Research and Human Retroviruses. 19: 1105-1113. 2003.
52. Hino, S., Katamine, S., Miyamoto, T., Doi, H., Tsuji, Y., Yamaba, T., Kaplan, J. E.,
Rudolph, D. L. and Lai, R. B. Association between maternal antibodies to the external
envelope glycoprotein and vertical transmission of human T-lymphocytic virus type-1. J. Clin.
Invest. 95: 2920-2925. 1995.
53. Yoshinaga, M., Yashiki, S., Oki, T., Fujiyoshi, T., Nagata, Y. and Sonoda, S. A maternal
risk factor for mother-to-child HTLV-1 transmission: viral antigen-producing capacities in
culture of peripheral blood and breast milk cells. Jpn. J. Cancer Res. 86: 649-654. 1995.
54. Buehring, G. C. Choi, K. Y. and Jensen, H. M. Bovine leukemia virus. In humans breast
tissues. Breast Cancer Res. 3, S1: A14. 2001.
55. Brenner, J., Meirom, R., Avraham, R., Savir, D. and Trainin, Z. Trial of two methods of the
eradication of bovine leucosis virus (BLV) infection from two large dairy herds in Israel. Isr. J.
Vet. Med. 44: 168- 175. 1988.
56. Trainin, Z., Brenner, J., Meirom, R. and Ungar-Waron, H. Detrimental effect of bovine
leukemia virus (BLV) on the immunological state of cattle. Vet. Immunol. Immunopathol.
54:293-302. 1996.
57. Harold, V. Retroviruses. Science, 240: 1427-1435. 1988
58. Da, Y., Shank, R. D., Stewart, J. A., Levin, H. A. Milk and fat decline in bovine leukemia
virus-infected Holstein cattle with persistent lymphocytosis. Proc. Natl. Acad. Sci. USA 14:
6538-6541. 1993.
59. Motton, D. D. and Buerhing, G. C. Bovine leukemia virus alters growth properties and
casein synthesis in mammary epithelial cells. J. Dairy Sci. 86: 2826-2833. 2003.
60. Buerhing G. C., Kramme, P. M. and Schultz, R. D. Evidence of bovine leukemia virus in
mammary epithelial cells of infected cows. Lab Invest. 71: 359-365. 1994.
61. Greger, M. Have millions of American been "infected with a cow cancer virus"?
www.veganmd.or/leukemia.html
62. Ruppanner, R., Behymer, D. E., Paul, S., Miller, J. M. and Theilen G. A strategy for
control of bovine leukemia virus infection test and corrective management. Can. Vet. J. 24: