Bovine leukemia virus

Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 HTLV-I. The natural host of BLV is cattle. BLV integrates into the genomic DNA of B-lymphocytes as a DNA intermediate (the provirus). Besides structural and enzymatic genes required for virion production, BLV contains an oncogene coding for a protein called Tax and expresses microRNAs of unknown function.^[1] In its natural host (the cattle) leukemia is rare (about 5% of infected animals) but lymphoproliferation is rather frequent (30%). Because the oncogenic properties of the virus were discovered early, a search for evidence of pathogenicity in humans started soon after discovery. Mostly farm workers drinking raw milk were tested for disease, especially for leukemia.^[2][3] It was discovered in 2003 that some humans carry antibodies reactive to BLV.^[2] In 2014, researchers discovered the presence of BLV positive cells in the human breast tissue.^[4] A case-controlled study was published in 2015 which suggests a possible association between breast cancer, and BLV.^[5] However, more recently, another case-control study conducted on Chinese patients did not find any association between BLV and breast cancer.^[6] In addition an exhaustive analysis of 51 whole genomes of breast cancers do not show any trace of BLV DNA and thus excludes a clonal insertion of BLV in breast tumor cells and strongly argues against an association between BLV and breast cancer.^[7]

History

High prevalence of virus was found from testing by USDA. "As part of the 2007 dairy study, bulk tank milk was collected from 534 operations with 30 or more dairy cows and tested with an Enzyme Linked-Immunosorbent Assay (ELISA) for the presence of antibodies against BLV. Results showed that 83.9 percent of U.S. dairy operations were positive for BLV (table 1)."^[8] BLV infection can be detected by ELISA or PCR.

In Europe attempts were made to eradicate the virus by culling infected animals. The first country considered to be free of infection was Denmark. Soon the United Kingdom followed. Like the North American states, those of the Eastern block in Europe did not try to get rid of the virus. But the Eastern Europe states started to become leukosis free after the political changes at the end of the last century. A quote from a USDA fact sheet, "The high individual animal prevalence of BLV reported in the Dairy 1996 study suggests that testing and culling seropositive animals may not be a cost effective method to control the disease. Instead, preventing disease transmission by implementing preventive practices would likely be more cost-effective."^[8]

Natural infection of animals other than cattle and buffalo are rare, although many animals are susceptible to artificial infection. After artificial infection of sheep most animals succumb to leukemia. Rabbits get a fatal AIDS-like disease similar to Pasteurella, different from the benign human snuffles. It is not known whether this naturally occurring rabbit disease is linked to BLV infection. "Although several species can be infected by inoculation of the virus, natural infection occurs only in cattle (Bos taurus and Bos indicus), water buffaloes, and capybaras. Sheep are very susceptible to experimental inoculation and develop tumours more often and at a younger age than cattle. A persistent antibody response can also be detected after experimental infection in deer, rabbits, rats, guinea-pigs, cats, dogs, sheep, rhesus monkeys, chimpanzees, antelopes, pigs, goats and buffaloes."^[9]

Some long term studies may be necessary, as there appears to be a correlation in instances of cancer among butchers and slaughterhouse workers.^[3] Several studies have been carried out in an attempt to determine whether BLV causes disease in humans, especially through the consumption of milk from infected cows. In 2003, research was published which demonstrated that 39% of 257 human volunteers had antibodies reactive to the BLV p24 capsid protein, contrary to previous findings.^[2][3] In 2014, a research team from University of California, Berkeley discovered the presence of BLV positive cells in the human mammary secretory epithelium.^[4] A case-controlled study published in late 2015 by the same team has demonstrated an association between the prevalence of BLV positive cells in breast tissue and breast cancer.^[5] However, two recent studies demonstrated the absence of BLV in breast cancer tissue thus showing the lack of association between BLV infection and breast cancer.^[6][7]

Research

Because of the close relationship between BLV and HTLV-I, the research on BLV is important. One can use the experience with BLV for understanding HTLV-I induced diseases like ATL the adult T-cell leukemia and HMS/TSP like neurological disorders. A number of case-control studies have been conducted recently, however the research in BLV related diseases is not as extensive as with other virus related diseases.^[9]

Transmission

Many potential routes of BLV transmission exist. Transmission through procedures that transmit blood between animals such as gouge dehorning, vaccination and ear tagging with instruments or needles that are not changed or disinfected between animals is a significant means of BLV spread. Rectal palpation with common sleeves poses a risk that is increased by inexperience and increased frequency of palpation. Transmission via colostrum, milk, and in utero exposure is generally considered to account for a relatively small proportion of infections.^[10] Embryo transfer and artificial insemination also account for a small number of new infections as long as common equipment and/or palpation sleeves are not used. While transmission has been documented via blood feeding insects, the significance of this risk is unclear. The bottom line appears to be that transmission relies primarily on the transfer of infected lymphocytes from one animal to the next and that BLV positive animals with lymphocytosis are more likely to provide a source for infection.

In general BLV causes only a benign mononucleosis-like disease in cattle. Only some animals later develop a B-cell leukemia called enzootic bovine leukosis. Under natural conditions the disease is transmitted mainly by milk to the calf. Infected lymphocytes transmit the disease from the donor to the recipient. Virus particles are difficult to detect and not used for transmission of infection.

Clinical signs of bovine leukosis and diagnosis

Conjunctival prolapse is a sign of bovine leukosis

The variety of organs where white blood cells occur explains the many symptoms: enlargement of superficial lymph nodes, a digestive form, a cardiac form, a nervous form, a respiratory form, and others.^[11] Lymph node enlargement is often an early clinical sign.^[12] An unexpected clinical finding is protrusion of the conjunctival membrane, due to enlargement of retro-ocular lymph nodes.^[12]

Diagnosis relies on agar gel immunodiffusion, ELISA and PCR. Post-mortem findings are characteristic and include widespread white tumours in most organs.^[12]

BLV infection in humans can be identified by testing for antibodies against BLV using the immunoblotting and searching for antibodies against the purified recombinant p24 capsid protein. This protein acts as an antigen for the IgG antibodies.^[4][9]

Treatment and control

No apparent treatment is available for the disease.^[12]

Testing and removing positive animals from the herd is one method of control. In herds where the disease is widespread, it is important to limit spread by avoiding contact with blood between animals.^[12]

Researchers have been working on developing an attenuated provirus vaccine for bovine.^[13][14] The theory is to create a provirus with a deletion in the pathogenic gene that confers oncogenesis (tax). This vaccine would be able to induce a persistent anti-BLV immune response through maintaining a low level of infectivity, while preventing the risk of infection by the wild-type virus which maintains the ability to drive oncogenesis.^[13][14] However, attempts thus far have not been able to create a vaccine that is easily transmitted from mother to offspring.^[13][14]

See also

• Bovine leukaemia virus RNA packaging signal

References

1. ↑ Nicolas Rosewick; Mélanie Momont; Keith Durkin; Haruko Takeda; Florian Caiment; Yvette Cleuter; Céline Vernin; Franck Mortreux; Eric Wattel; Arsène Burny; Michel Georges & Anne Van den Broeke (2013). "Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma". Proceedings of the National Academy of Sciences. 110 (6): 2306–11. doi:10.1073/pnas.1213842110. PMC 3568357. PMID 23345446. 
2. 1 2 3 Buehring GC, Philpott SM, Choi KY (December 2003). "Humans have antibodies reactive with Bovine leukemia virus". AIDS Res. Hum. Retroviruses. 19 (12): 1105–13. doi:10.1089/088922203771881202. PMID 14709247. 
3. 1 2 3 Johnson ES (2005). "Assessing the role of transmissible agents in human disease by studying meat workers". Cellscience Reviews. 2 (1). ISSN 1742-8130. Archived from the original on 2006-10-18. 
4. 1 2 3 Buehring, Gertrude Case; Shen, Hua Min; Jensen, Hanne M.; Choi, K. Yeon; Sun, Dejun; Nuovo, Gerard (2014-05-01). "Bovine Leukemia Virus DNA in Human Breast Tissue". Emerging Infectious Diseases. 20 (5): 772–782. doi:10.3201/eid2005.131298. PMC 4012802. PMID 24750974. 
5. 1 2 Buehring, Gertrude Case; Shen, Hua Min; Jensen, Hanne M.; Jin, Diana L.; Hudes, Mark; Block, Gladys (2015-09-02). "Exposure to Bovine Leukemia Virus Is Associated with Breast Cancer: A Case-Control Study". PLoS ONE. 10 (9): e0134304. doi:10.1371/journal.pone.0134304. PMC 4557937. PMID 26332838. 
6. 1 2 Zhang, Rong (10 October 2016). "Lack of association between bovine leukemia virus and breast cancer in Chinese patients". Breast Cancer Research. doi:10.1186/s13058-016-0763-8. PMC 5057430. PMID 27724949. 
7. 1 2 Gillet, Nicolas A.; Willems, Luc (4 November 2016). "Whole genome sequencing of 51 breast cancers reveals that tumors are devoid of bovine leukemia virus DNA". Retrovirology. 13 (1). doi:10.1186/s12977-016-0308-3. PMC 5095936. PMID 27814725. 
8. 1 2 "Bovine Leukosis Virus on U.S. Dairy Operations, 2007" (PDF). NAHMS Dairy 2007. U.S. Department of Agriculture. 
9. 1 2 3 OIE (2010). "Chapter 2.4.11 Enzootic bovine leukosis" (PDF). Manual of Diagnostic Tests and Vaccines for Terrestrial Animals. World Organisation for Animal Health (OIE). 
10. ↑ Meas, Sothy; Usui, Tatsufumi; Ohashi, Kazuhiko; Sugimoto, Chihiro; Onuma, Misao (2002-01-23). "Vertical transmission of bovine leukemia virus and bovine immunodeficiency virus in dairy cattle herds". Veterinary Microbiology. 84 (3): 275–282. doi:10.1016/s0378-1135(01)00458-8. PMID 11731179. 
11. ↑ D.C. Blood; J.A. Henderson; O.M. Radostits (1979). Veterinary Medicine (5th ed.). London: Baillière Tindall. pp. 611 (Leucosis in cattle and other species). ISBN 0-7020-0718-8. 
12. 1 2 3 4 5 Bovine Leukaemia Virus reviewed and published by WikiVet, accessed 10 October 2011.
13. 1 2 3 Gutiérrez, Gerónimo; Rodríguez, Sabrina M.; de Brogniez, Alix; Gillet, Nicolas; Golime, Ramarao; Burny, Arsène; Jaworski, Juan-Pablo; Alvarez, Irene; Vagnoni, Lucas (2014-06-01). "Vaccination against δ-retroviruses: the bovine leukemia virus paradigm". Viruses. 6 (6): 2416–27. doi:10.3390/v6062416. PMC 4074934. PMID 24956179. 
14. 1 2 3 Barez, Pierre-Yves; de Brogniez, Alix; Carpentier, Alexandre; Gazon, Hélène; Gillet, Nicolas; Gutiérrez, Gerónimo; Hamaidia, Malik; Jacques, Jean-Rock; Perike, Srikanth (2015-11-24). "Recent Advances in BLV Research". Viruses. 7 (11): 6080–8. doi:10.3390/v7112929. PMC 4664998. PMID 26610551. 

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