African Journal of
Biotechnology

  • Abbreviation: Afr. J. Biotechnol.
  • Language: English
  • ISSN: 1684-5315
  • DOI: 10.5897/AJB
  • Start Year: 2002
  • Published Articles: 12496

Review

Enzootic bovine leukosis and the risk to human health

Axel Villalobos-Cortés
  • Axel Villalobos-Cortés
  • Instituto de Investigación Agropecuaria, Laboratorio de Análisis y Biología Molecular Aplicada, Ciudad de Saber Edificio 221, Republic of Panama.
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  •  Received: 15 October 2016
  •  Accepted: 21 March 2017
  •  Published: 12 April 2017

 ABSTRACT

The bovine leukemia virus (BLV) was first reported as enzootic bovine lymphosarcoma in Eastern Europe in the late 19th century, highlighted by the presence of slightly yellow nodules in the enlarged spleen of cattle. It was believed to be an infectious disease because it spreaded through the herds. With changes observed in sensitivity of diagnostic techniques, the opinion that “BLV does not infect humans” starts to change after more than two decades.  Several researches tried to link the BLV and human health in some studies in which BLV and human breast cancer have been shown. Studies about the possible routes of infection and to explain the genetic transformation processes in humans are raised. Multiple reports on this disease that link it to human health concluded on the need for a new mind set to understand relation between BLV and human health so as to improve the prevention, control and eradication of cattle herds.

 

Key words: Zoonotic disease, bovine leukemia virus, polymerase chain reaction (PCR), cancer.


 INTRODUCTION

For years, the disease known as enzootic bovine leukemia (EBL) has been defined as a sickness limited to cattle, particularly dairy cattle. Researchers around the world have made significant efforts to demonstrate, without a doubt, that this disease is not related to any pathology in humans (Gilden et al., 1975; Donham et al., 1977; Burridge, 1981). With the emergence of new diagnostic technologies, the detection of a large diversity of pathogenic agents has improved, including the said disease. With the currently obtained results (Buehring et al., 2003; Buehring et al., 2007; Nikbakht et al., 2010; Mesa et al., 2013; Buehring et al., 2014; Buehring et al., 2015; Villalobos, 2016), doubts have once more emerged about whether this virus is capable of affecting human health. The objective of this review is to provide relevant information on this disease from its discovery in 1871 to 2016, including the history, classification and epidemiology, mechanisms of action of the virus to cause harm, cancer and its association with the virus, entry routes and mechanisms of cellular transformation, all of which cast new light on the implication of bovine leukemia virus (BLV) in human health. The definitive response on this subject still lacks a categorical response.


 HISTORY

Bovine leukemia virus was first reported as enzootic bovine lymphosarcoma in Eastern Europe in the late 19th century, highlighted by the presence of slightly yellow modules in a splenomegaly observed in cattle; it was believed to be an infectious disease because it spread through herds (Leisering, 1871; Buehring et al., 2014). In 1917, its transmission through an infectious agent was demonstrated (Schwartz and Levy, 1994). Subsequently, Miller et al. (1969) used electron microscopy to demonstrate the presence of the viral particle within a lymphocyte in cows with lymphosarcoma; finally, using Koch’s postulates, the causal association between the virus and enzootic bovine lymphosarcoma was successfully demonstrated (Olson et al., 1973; Olson, 1974). The first studies that showed evidence on the possible transmission of BLV in human cells and other species were conducted by Graves and Ferrer (1976), who obtained samples from cows infected with BLV in a state of persistent lymphocytosis that were cultivated in boundary cap (BC) cells; these samples proceeded to infect cell cultures of humans, simians (chimpanzees and rhesus), canines, sheep, goats and bats. In all of the cell cultures of the mentioned species, production of the complete virus was observed. The authors concluded that BLV can infect cells of the rhesus monkey, chimpanzees and humans, and it merits special attention in terms of its potential as a biohazard towards human beings.
 
Subsequently, Slavikova et al. (1987) isolated 60 clones of human myeloma B cells that were infected with BLV­. Amongst the 60 clones evaluated, two harboured proviral sequences and the presence of virus proteins, confirming their expression ability in human cells in vitro. Altaner et al. (1989) obtained similar results using clones of foetal sheep cells (FLK) infected with virus to which human neuronal cells were exposed. The data showed that the neuronal cells could be infected by direct contact and the virus is capable of replicating itself; therefore, in vitro, these cells are susceptible and permissive to BLV. During the 1990s, Ursin et al. (1990) showed interest in the possibility that there is a risk to human health from BLV. These authors presented a prospective study in which a possible association between the consumption of cow’s milk and cancer was investigated. The study followed 15,914 individuals for a period of eleven years, of whom 1,422 were diagnosed with cancer. The types of cancer evaluated were cancer of the lip, mouth, throat, oesophagus, stomach, colon, rectum, pancreas, larynx, respiratory tract, breast, cervical-uterine, ovarian, prostate, kidney, bladder, melanoma, skin cancer, thyroid, lymph organs, multiple myeloma and leukaemia. Risk factors considered were active tobacco consumption and ex-smokers and alcohol, meat, egg and coffee consumption. Although the investigation did not identify an association between milk consumption and total incidence of cancer, there was a strong association between milk consumption (two cups daily) and cancer in lymph organs, particularly lymphosarcoma, the same condition that is present in cattle. The study also  found  a slight positive association with kidney cancer and female reproductive organs, except for cervical-uterine cancer. In 1990, an increase in cancer was observed by Davis et al. (1990) in the agricultural population of several countries (Germany, Italy, United States, Japan, England and Wales), particularly in the lymphatic and haematopoietic system compared to the general population; thus, special attention was demanded on this topic (Blair et al., 1992). However, in other studies, such as those by Fritschi et al. (2003) in meat workers or reports by Sellers et al. (2008) on the risk of consuming unpasteurized milk, there have not been consistent results on the risks of contracting any type of cancer in particular.     


 CLASSIFICATION, HOSTS AND REPLICATION STRATEGY OF THE VIRUS

BLV (Retroviridae family; Orthoretrovirinae subfamily, Deltaretrovirus genus) is an exogenous retrovirus, responsible for EBL, which is the most common neoplastic disease in cattle worldwide (Schwartz and Levy, 1994; Dequiedt et al., 1999; Beyer et al., 2002; Moratorio et al., 2013). BLV is related to human T-lymphotropic virus types 1, 2 and 3 (HTLV 1, 2 and 3) and primate T-lymphotropic virus types PTLV 1, 2 and 3 (Gelmann et al., 1983; Tanaka et al., 1990; Heenemann et al., 2012). Infection is transmitted horizontally, through the transfer of infected cells by direct contact, ingestion of colostrum, milk and possibly through bloodsucking insects (Ferrer et al., 1978; Gillet et al., 2007). Vertical transmission (cow to calf) has also been demonstrated transplacentally (Ferrer, 1979; Van der Maaten et al., 1981; Romero et al., 1983; Lassauzet et al., 1991; Hübner et al., 1997). Although the virus has been demonstrated to have cattle as its main host, infection also occurs in buffalo and capybaras (Schwartz and Levy, 1994). Sheep and goats have been experimentally infected and have been routinely used in the investigation of BLV, with the particularity that goats develop cancer faster than cattle (Schwartz and Levy, 1994; Gillet et al., 2007; Merimi et al., 2007); therefore, it is proposed that the mechanisms of leukemogenesis in cattle and goats are likely different (Graves and Ferrer, 1976; Djilali and Parodi, 1989).
 
The propagation of BLV in the host occurs through two distinct processes. In the first process, the infectious cycle results from the virion coupling with the target lymphocyte, entry of the single-stranded viral RNA, reverse transcription and integration as a provirus into the host genome (also known as the infectious cycle). The second replication strategy depends on the management of cellular proliferation using viral regulatory proteins such as Tax. The two routes of viral replication produce a group of infected cell populations composed of distinct clones (Gillet et al., 2013). In the same study, Gillet et al. (2013) also demonstrated that BLV is initially  directed  to transcribed regions of the genome for its integration; afterwards, a massive selection of clones is produced during primary infection, disfavouring proviruses located near genes; however, the abundance of long-term clones benefits transcriptional activity of the genomic region surrounding the provirus.


  EPIDEMIOLOGY AND DIAGNOSIS OF THE EBL

The Guaymí and Guabalá are breeds reported in 2010 (Villalobos et al., 2010) and have been the subject of various studies in order to preserve them and use them for the production of milk and meat (Delgado et al., 2012; Martinez et al., 2012). With the emergence of an outbreak of EBL in native cattle in Panama in 2011, new diagnostic protocols were developed in order to replace the agar gel immunodiffusion (AGID) by better methods such as blocking enzyme-linked immunosorbent assay (ELISA) and nested polymerase chain reaction (PCR), and the development of genetic studies of disease resistance (Villalobos and Gonzalez, 2015). With the recent reports of the virus in human beings, a new line of research was created by the use of gene markers env, gag and Tax in human lymphocytes (Villalobos, 2016).


 THE ZOONOTIC POTENTIAL OF BLV

In a study conducted by Buehring et al. (2001) under the premise that BLV is present in many of the meat products and milk on the market and because the incidence of breast cancer is higher in countries with a high consumption of food products from bovine species, the authors found that many humans possess antibodies against BLV, particularly the envelope glycoprotein (gp51) and capsule protein (p24), suggesting the possibility of infection with the virus. These same authors, using immunohistochemistry and PCR in situ in patients diagnosed with cancer and subject to surgical excision, showed that most mammary tissues studied presented evidence of a proviral genome of BLV, and four of the 27 samples were positive for the virus capsule protein.
 
With changes observed in low sensitivity techniques, such as complement fixation or agar gel immunodiffusion (AGID) in the 1970s and 1980s (Gilden et al., 1975; Donham et al., 1977; Burridge, 1981), compared to more modern techniques such as the enzyme linked immunosorbent assay (ELISA) and immunoblotting, the opinion that had prevailed for more than two decades that “BLV is not transmissible to humans and no disease in humans has been attributed to BLV” could be changing. In a study performed at the University of Berkeley, California, by Buehring et al. (2003) based on serum samples of 257 people, four isotypes of antibodies were used (IgG1, IgM, IgA and IgG4) to detect the capsule (p24) antigen of BLV. At least one reactive isotype to the protein was detected in 74% of the evaluated  population. Although the investigation did not conclude there was infection to humans, it again opens the debate on the possibilities of additional studies with techniques such as real time PCR because of the possibility that the reaction was in response to denatured antigens from heat action in ingested foods. Conversely, Lee et al. (2005) investigated the possible relationship between leukaemia, lung cancer and meat consumption in Korea, using new primer sets of the envelope gene; the results were negative, indicating that virus infection did not occur in any of the cases.  
 
To provide evidence of possible zoonotic behaviour of BLV, Ochoa-Cruz et al. (2006) selected 56 cases diagnosed with ductal carcinoma, of which the immunoperoxidase assay was applied for the purpose of detecting glycoprotein gp51 of BLV in the cytoplasm of tumour cells. The technique showed that 7% of samples were positive for gp51, demonstrating the presence of BLV in humans with the ability to produce viral protein; the appearance of this molecule implies that the active provirus inserted in the genome is capable of producing structural viral proteins to assemble progeny. Subsequently, Buehring et al. (2007) used in situ PCR with primers of the Tax region of BLV to evaluate 213 samples of mammary gland tissue sections fixed with formalin distributed in 110 women with breast cancer and 103 controls (women without a history of breast cancer). The investigation showed positive reactions to BLV in 59% of the cases of women with breast cancer and in 29% of the control cases. Amongst the samples from women with breast cancer, 69% showed proviral BLV DNA in the accompanying non-malignant mammary epithelium, suggesting that the development of cancer may be an exceptional case, delayed within a population of cells infected with BLV in mammary tissue (field effect). These data provide a first promising step in the establishment of a causal role of BLV in human breast cancer. 
 
Another investigation in which serological (ELISA) and genomic (PCR) techniques were used was conducted by Nikbakht et al. (2010) in the School of Veterinary Medicine of the University of Tehran; this study analysed 454 samples of human patients without any clinical symptoms in particular. Based on the serological test, 57 patients (12.5%) were diagnosed as positive. For the PCR test, 77 patients were evaluated (57 positive and 20 negative to the ELISA test). It was possible to isolate provirus in 12.3% of the 57 positive ELISA samples. Although the examination revealed the presence of provirus, the authors remained cautious in the conclusions because the provirus may not necessarily be integrated into the genome but rather be a non-integrated element (episome); in the latter case, people may not be actively infected. A study similar to that conducted by Buehring et al. (2007) was developed by Mesa et al. (2013) in Colombia with 106 mammary tissue samples from female patients (53 patients were positive for breast cancer and 53 were negative). A PCR analysis was performed on these patients to detect the gag segment of BLV. Of the analysed samples, 35% of the patients positive for breast cancer were positive for gag amplification and 45% of the patients were negative. Given the discovery of antibodies against BLV in humans, Buerhing et al. (2014) used human mammary tissue for BLV infection tests using liquid phase PCR (L-PCR), sequencing, in situ PCR and immunohistochemistry (IHC). The studies focused on mammary tissue because in the original host, bovine cattle, BLV DNA and p24 protein are found in greater abundance than in lymphocytes. The findings of this investigation conclude that there is evidence showing that the BLV DNA and protein found present a high likelihood of constituting the in vivo presence of BLV in humans. Subsequently, Buehring et al. (2015) conducted a study on the cause-effect relationship between BLV and breast cancer in 239 patients with positive and negative records, using anatomopathological studies of mammary tissue. The presence of the virus was observed in 59% of malignant tissues, 38% of tissues with premalignant changes and 29% of tissues from normal controls. The study concluded that there is a highly significant cause-effect relationship. However, the authors also noted that one control study is not conclusive on its own, and validation from other investigators is required. In a randomized study conducted in a region in Panama by Villalobos (2016), 20 patients were sampled anonymously in order to detect the gag gene of enzootic bovine leukosis virus and 75% of them were positive. A larger project is currently being conducted with the aim of increasing the number of human patients and the virus markers like Tax, env and pol. Furthermore, a prospective study is required that demonstrates that viral infection precedes the development of cancer to support the idea of causality of the virus towards breast cancer. In light of the possible public health consequences of BLV in humans, future research should address how humans are infected by BLV, the frequency with which BLV infection is produced in different populations and whether the virus is associated with disease in humans.


 ROUTES OF BLV ENTRY INTO THE HUMANS

As the presence of the virus within humans has been successfully demonstrated, whether by indirect methods such as ELISA and immunoblotting or direct methods such as PCR, several entry routes have now been proposed, such as direct contact with animals or animal products. The consumption of unpasteurized milk, artisanal cheeses and improperly cooked meat could be entry vehicles of the virus in populations likely to be exposed in rural areas such as Panama, Peru, Mexico and the United States, where a very common practice is ingesting   milk    from    cows.   For    example,   a   study conducted in the United States by Oliver et al. (2009) shows that between 35 and 60% of families and employees at farms ingest unpasteurized milk, and cattle herds infected with BLV are found throughout the world. In the United States, close to 38% of cattle herds, 84% of dairy herds and 100% of herds of large-scale dairy operations are infected (USDA, 1999, 2008). The detection of antibodies due to the consumption of foods derived from the bovine species had previously been reported by Barnes et al. (1988), particularly the reactivity from isotypes IgG2 and IgG4 towards antigens of bovine milk. Buehring et al. (2003) reported using the isotype IgG4 in the reactivity to BLV. Notably, viral particles from BLV denatured by pasteurization or heat can cause reactivity from the human immune system; however, it is not possible to differentiate them from un-denatured viral particles (Buehring et al., 2003). Another possible entry route could be injection of biological products contaminated by BLV, for example, with the development of anti-hemoparasite vaccines (Callow et al., 1997) and the incidence of many vaccines contaminated with BLV, as reported by Rogers et al. (1988), which forced the implementation of more rigorous diagnostic techniques against BLV in Australia. However, there are no reports of BLV contamination or production of the virus in in vitro cell lines for vaccines (Buehring et al., 2003). Furthermore, epithelial cells are identified as the entry route of the virus, through a genome integration process and the recognition of similar receptors to those of cattle (BVLRcp1) or through the interference of other unidentified molecules such as IgM, CD5+ and CD11b integrins, similar to experimental infection in studies on goats (Mesa et al., 2013). Importantly, once a zoonotic virus enters the human population, the majority are capable of dispersing amongst the population, a process that constitutes the most severe threat for human health (Christou et al., 2011). On this line of thought, BLV is known for crossing towards other species easily; the virus naturally infects capybara, Zebu cattle water buffalo, and it has experimentally infected sheep, goats, pigs, rabbits, rats and chickens (Schwartz and Levy, 1994). Moreover, human cells (fibroblasts) are susceptible to infection with BLV in vitro (Diglio and Ferrer, 1976). 


 MECHANISM OF LEUKEMOGENESIS BY BLV

Leukemogenesis mechanisms (induction of leukemia) through animal retroviruses that belong to the Alpharetrovirus and Gammaretrovirus genera induce tumour production by two mechanisms: activation of a viral oncogene or insertion of a gene from the cell, such as a proto-oncogene (Weiss et al., 1985). However, deltaretroviruses such as BLV lack a known oncogene (Sagata et al., 1984). Most of the studies on leukemogenesis induced by BLV have focused on the Tax   protein    because     it    is    considered   a    potent transcriptional activator of viral gene expression. In addition to its function as a transcriptional activator, the Tax protein induces the immortalization of fibroblasts of the rat embryo (Willems et al., 1990, 1998). This ability to induce immortalization may be the first step in the transformation process mediated by BLV. However, once the cattle are infected and during the latent period, the expression of BLV is blocked at the transcriptional level (Kettmann et al., 1982; Lagarias and Radke, 1989). Such repression appears to be very important for the escape of BLV from the immune surveillance system of the host, and subsequently only a small proportion of infected animals would rapidly develop the terminal stage of the disease (Gillet et al., 2007). In fact, transcription of the BLV genome in fresh tumour cells or in peripheral mononuclear cells (PBMCs) in fresh blood of infected individuals is almost undetectable by conventional techniques (Kettmann et al., 1982; Tajima et al., 2003; Tajima and Aida, 2005).


 LEUKEMOGENESIS AND PX REGION

All retroviruses possess the genes gag, pro, pol and env, which encode the internal structural proteins, viral protease, reverse transcriptase and envelope glycoproteins of the virion, respectively, and are essential for the production of infectious viral particles. The genes are flanked by two identical long terminal repeats, LTRs (Alfaro et al., 2012). Although the genome sequences of BLV and HTLV-1 differ, they have a sequence in common called pX that is located between the env gene and the 3’LTR region that encodes a regulatory gene. In both viruses, the regulatory proteins Tax and Rex are encoded in the pX region. The R3 and G4 proteins are encoded in the pX region of BLV, whereas p12I, p13II and p30II are encoded in the pX region of HTLV-1 (Sagata et al., 1984; Franchini et al., 2003). The pX sequences do not originate from the host cells and thus it is not an oncogene. In both BLV and HTLV-1, the Tax protein acts as an activator of transcription with oncogenic potential, and Rex interferes with the exportation of messenger RNA of both viruses from the nucleus (Derse, 1987; Willems et al., 1987; Felber et al., 1989; Katoh et al., 1989; Willems et al., 1990; Kashanchi and Brady, 2005; Matsuoka and Jeang, 2011). In cattle, the R3 and R4 proteins contribute to the maintenance of a high viral load (Willems et al., 1994; Florines et al., 2007). Furthermore, p12I and p13II proteins from HTLV-1 are similar in some functions to R3 and G4, respectively. p12I resembles R3 in that both are maintained in the nucleus and contribute to infectivity of the virus (Collins et al., 1998; Gillet et al., 2007); the p13II protein resembles the G4 protein because both bind to the farnesyl pyrophosphate synthetase, which farnesylates ras (Lefebvre et al., 2002) in addition to promoting ras dependent apoptosis (Hiraragi et al., 2005). Similarly, suppressions have  been observed in the sequences of gag, pol and env in all of the BLV-positive panel samples, and the presence of LTR sequences and Tax in these samples is consistent with the results reported for HTLV-1, which are associated with escape from immune surveillance (Kamihira et al., 2005; Buehring et al., 2014).


 MECHANISMS OF CELLULAR TRANSFORMATION

Given the reports of the presence of BLV found integrated to the genome or as an episome in humans in the United States by Buehring et al. (2007), in Iran by Nikbakht et al. (2010) and in Colombia by Ochoa-Cruz et al. (2006), Mesa et al. (2013) and Buehring et al. (2014), possible mechanisms of transformation in mammary tissue must be proposed. These include involvement of the Tax gene in oncogenic processes in vivo and in vitro, such as viral transcription and increased expression in the proportion of the Bcl-2 protein (a proto-oncogene) over its protein homologue, Bax, which are related to resistance to apoptosis and the production of leukaemia in infected cows (Takahashi et al., 2005). A similar mechanism of resistance to apoptosis and chronic lymphocytic leukaemia occurs in humans (Pepper et al., 1997). Some authors mention that in the BLV genome, there is no preference for a particular site in the host genome (Murakami et al., 2011), and BLV could integrate itself in active sites associated with the control of cell division (Fulton et al., 2006; Klener et al., 2006). However, Gillet et al. (2013) demonstrated that BLV and HTLV-1 have surprisingly similar genomic regions where it is expected that the provirus of both viruses is inserted with a greater likelihood in their respective hosts. These insertion sites are the regions transcribing Pol II (polymerase) and Pol III, the regions close to the CpG islands, tRNA genes (transfer RNA) and tRNA pseudogenes. Similarly, in a study conducted by Elemans et al. (2014) on the mortality rate of cytotoxic T lymphocytes CD8+ (CTL) against infection of BLV and HTLV-1, both viruses are in the lowest range observed in the literature. This similarity could lead to finding similar mechanisms of action of BLV in humans.
 
Actions of the virus on the block of tumour suppressor and apoptosis genes could be a possible cause, as Melana et al. (2002) reports in breast cancer in the case of mouse mammary tumour virus (MMTV). Mutations of the p53 gene have been reported in 20% of women with breast cancer, and 30% of malignant processes in humans have been attributed to mutations of the oncogene ras (Javier and Butel, 2008).
 
Given the possibilities of action of the virus in humans, cases of benign, pre-malignant and malignant cell transformations and cases of latent virus presenting in apparently healthy patients could possibly be found without presenting changes in tissue, as shown in several previously mentioned reports and  in  the  bovine  species or other retroviruses such as HIV and HTLV (Mesa et al., 2013). An additional finding has been made in recent years by Kinkaid et al. (2012), who demonstrated the presence of micro RNA (miRNA) in BLV. These miRNAs are small regulatory sequences encoded by most eukaryotic cells and some viruses that collectively have DNA type genomes. The miRNA type BLV-miR-B4 has been identified in BLV, which is transcribed by RNA polymerase III (pol III). The BLV-MiR-B4 shares partial identity of its sequences. It also shares target sequences with the miRNA of the bovine host (miR-29), and because the overexpression of miR-29 is associated with neoplasias of B lymphocytes that resemble tumours associated with BLV, a possible mechanism is suggested that contributes to the tumour genesis of BLV, similar to the participation of cell transformation in humans. Currently, six viruses are causally associated with cancer in human patients: The Epstein-Barr virus (EBV), human T-lymphotropic virus type 1 (HTLV 1), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV) and human herpes virus 8 (HHV-8). However, given the growing research, using more advanced techniques such as ELISA, immunoblotting, nested PCR and RT-PCR, BLV is a new candidate to join the list of potentially hazardous viruses to human health and particularly cancer of the mammary gland (Rees, 2012). Other viruses together with BLV have also been proposed as potentially hazardous to human health, such as MMTV and cytomegalovirus (Lawson, 2006; Mason et al., 2011); thus, a change of thinking on the relationship between cancer and viruses is necessary. There is research in progress that could resolve various hypotheses that remain unsupported; however, as long as new lines are opened with methodologies that allow a better understanding of the action of the virus, particularly BLV and cancer in humans, new and better diagnostic, prevention and control methodologies of these diseases will continue to develop. Breast cancer occupies a significant position worldwide in terms of morbidity and mortality. Between 5 and 10% of all breast cancer cases are associated with hereditary factors. The rest are associated with other factors such as infections, of which 8% of the malignancy is reported in developed countries and an impressive 23% in developing countries.


 CONCLUSION

Considering the scientific facts on the high prevalence of the EBL virus in countries such as the United States, the consumption of milk, meat and animal by-products positive for the disease, the constant exposure to the virus, the immune response against it and, ultimately, the demonstrated presence of the virus in the human genome, it is clear that there is a real potential risk. It is necessary to direct greater investment in research; rethink a new vision on the risks to human health; and develop   programmes  of  diagnosis,  prevention,  control and eradication of the virus, particularly in countries with high prevalence. These steps may result in less exposure to the virus and a consequent reduction of the risk that it becomes, from the effects of evolution, a true zoonosis. 


 CONFLICT OF INTERESTS

The author has not declared any conflict of interests.



 REFERENCES

Alfaro Uera J, Ventura Lazaro J, Niegos Mingala.(2012). Detection of Enzootic Bovine Leukosis in Cattle using Nested Polymerase Chain Reaction Assay. Thai. J. Vet. Med. 42(3):319-324.
 

Altaner C, Altaneroyá V, Bán V, Niwa V, Yokoro K (1989). Human cells oľ neural origin are permissive for bovine leukemia virus. Neoplasma 35(6):691-695.

  
 

Barnes RM, Johnson PM, Finn R, and Harvey M (1988). Human serum antibodies reactive with dietary proteins. Int. Arch. Allergy Appl. Immunol. 87:184-188.
Crossref

  
 

Beyer J, Kollner B, Teifke JP, Starick E, Beier D, Reimann I, Grunwald U, Ziller M (2002). Cattle Infected with Bovine Leukaemia Virus may not only Develop Persistent B-Cell Lymphocytosis but also Persistent B-cell Lymphopenia. J. Vet. Med. B. 49:270-277.
Crossref

  
 

Blair A, Hoar S, Pearce N, Heineman E, Fraumeni J (1992). Clues to cancer etiology from studies of farmers. Scand. J. Work Environ. Health 18:209-215.
Crossref

  
 

Buehring GC, Choi KY, Jensen HM (2001). Bovine leukemia virus in human breast tissues. In. 23rd Congress of the International Association for Breast Cancer Research: (2001); Dusseldorf, Germany. BioMed Central Ltd: A14.
Crossref

  
 

Dusseldorf, Germany. BioMed Central Ltd: A14.

  
 

Buehring GC, Philpott SM, Choi KY (2003). Humans have antibodies reactive with Bovine leukemia virus. AIDS Res. Hum. Retroviruses 19(12):1105-1113.
Crossref

  
 

Buehring GC, Shen HM, Jensen H, Block G (2007). Bovine leukemia virus infection is significantly associated with risk of breast cancer. In: American Association for Cancer Research: Apr 14-18, 2007; Los Angeles, CA.

  
 

Buehring GC, Shen HM, Jensen HM, Jin DL, Hudes M, Block G (2015). Exposure to Bovine Leukemia Virus is associated with breast cancer: A Case- Control Study. Plos One 10(9):e0134304.
Crossref

  
 

Buehring GC, Shen HM, Jensen HM, Yeon Choi K, Sun D, Nuovo G (2014). Bovine Leukemia Virus DNA in Human Breast Tissue. Emerg. Infect. Dis. 20(5):772-782.
Crossref

  
 

Burridge MJ (1981). The zoonotic potential of bovine leukemia virus. Vet. Res. Commun. 5:117-126.
Crossref

  
 

Callow LL, Dalgliesh RJ, De Vos AJ (1997). Development of effective living vaccines against bovine babesiosis-the longest field trial? Int. J. Parasitol. 27:747-767.
Crossref

  
 

Christou L (2011). The global burden of bacterial and zoonotic infections. Clin. Microbiol. Infect. 17:326-330.
Crossref

  
 

Collins ND, Newbound, GC, Albrecht B, Beard, JL, Ratner L, Lairmore, MD (1998). Selective ablation of human T-cell lymphotropic virus type 1 p12I reduces viral infectivity in vivo. Blood 91:4701-4707.

  
 

Davis DL, Hoel D, Fox J, Lopez A. (1990). International trends in cancer mortality in France, West Germany, Italy, Japan, England and Wales, and the USA. Lancet 336:474-481.
Crossref

  
 

Delgado JV, Martinez AM, Acosta A, Alvarez LA, Armstrong E, Camacho E, Canon J, Cortes O, Dunner S, Landi V, Marques JR, Martín-Burriel I, Martínez OR, Martínez RD, Melucci L, Mu-oz JE, Penedo MC, Postiglioni A, Quiróz J, Rodellar C, Sponenberg P, Uffo O, Ulloa-Arvizu R, Vega-Pla JL, Villalobos A, Zambrano D, Zaragoza P, Gama LT, Ginja C (2012). Genetic characterization of Latin-American Creole cattle using microsatellite markers. Anim Genet. 43:2-10.
Crossref

  
 

Dequiedt F, Cantor GH, Hamilton VT, Pritchard SM, Davis WC, Kerkhofs P, Burny A, Kettmann R, Willems L (1999). Bovine leukemia virus-induced persistent lymphocytosis in cattle does not correlate with increased ex vivo survival of B lymphocytes. J. Virol. 73:1127-1137.

  
 

Derse D (1987). Bovine leukemia virus transcription is controlled by a virus-encoded trans-acting factor and by cis-acting response elements. J. Virol. 61:2462-2471.

  
 

Diglio CA, Ferrer JF (1976). Induction of syncytia by the bovine C-type leukemia virus. Cancer Res. 36:1056-1067.

  
 

Djilali S, Parodi AL (1989). The BLV-induced leukemia–lymphosarcoma complex in sheep. Vet. Immunol. Immunopathol. 22:233-244.
Crossref

  
 

Donham K, Van Der Maaten MJ, Miller JM, Kruse BC, and Rubino MJ (1977). Seroepidemiologic studies on the possible relationships of human and bovine leukemia. J. Natl. Cancer Inst. 59:851-853.
Crossref

  
 

Felber BK, Derse D, Athanassopoulos A, Campbell M, Pavlakis GN (1989). Cross-activation of the Rex proteins of HTLV-1 and BLV and of the Rev protein of HIV-1 and non reciprocal interactions with their RNA responsive elements. New Biol. 1:318-328.

  
 

Ferrer JF (1979). Bovine leukosis: Natural transmission and principles of control. J. Am. Vet. Med. Assoc. 175:(12)1281-1286.

  
 

Ferrer JF, Piper CE (1978). An evaluation of the role of milk in the natural transmission of BLV. Ann. Rech. Vet. 9:803-807.

  
 

Fritschi L, Fenwick S, Bulsara M (2003). Mortality and cancer incidence in a cohort of meatworkers. Occup. Environ. Med. 60(9):e4.
Crossref

  
 

Fulton B, Portella M, Radke (2006). Dissemination of Bovine Leukemia Virus-Infected Cells from a Newly In- fected Sheep Lymph Node. J. Virol. 80(16):7873-7884.
Crossref

  
 

Gillet N, Gutiérrez G, Rodriguez SM, de Brogniez A, Renotte N, Alvarez I, Karina T, Willems L (2013). Massive Depletion of Bovine Leukemia Virus Proviral Clones Located in Genomic Transcriptionally Active Sites during Primary Infection. PLoS Pathog 9(10), e1003687.
Crossref

  
 

Gelmann EP, Popovic M, Blayney D, Masur H, Sidhu G, Stahl RE, Gallo RC (1983). Proviral DNA of a retrovirus, human T-cell leukemia virus, in two patients with AIDS. Science 220(4599):862-865.
Crossref

  
 

Gilden RV, Long CW, Hanson M, Toni R, Charman HP, Oroszlan S, Miller JM, Van der Maaten MJ (1975). Characteristics of the major internal protein and RNA-dependent DNA polymerase of bovine leukemia virus. J. Gen. Virol. 29:305-314.
Crossref

  
 

Gillet N, Florins A, Boxus M, Burteau C, Nigro A, Vandermeers F, Balon H, Bouzar A, Defoiche J, Burny A, Reichert M, Kettmann R, Willems L (2007). Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human. Retrovirology 4(1):18.
Crossref

  
 

Graves D, Ferrer J. (1976). In Vitro Transmission and Propagation of the Bovine Leukemia Virus in Monolayer Cell Cultures. Cancer Res. 36:4152-4159.

  
 

Heenemann K, Lapp S, Teifke J, Fichtner D, Mettenleiter T, Vahlenkamp T (2012). Development of a Bovine leukemia virus polymerase gene-based real-time polymerase chain reaction and comparison with an envelope gene -based assay. J. Vet. Diagn. Invest. 24:649-655.
Crossref

  
 

Hiraragi H, Michael B, Nair A, Silic-Benussi M, Ciminale, V, Lairmore M (2005). Human T-lymphotropic virus type 1 mitochondrion-localizing protein p13II sensitizes Jurkat T cells to Ras- mediated apoptosis. J. Virol. 79:9449-9457.
Crossref

  
 

Hübner SO, Weiblen R, Moraes MP, Silva AM, Cardoso MJL, Pereira NM, Zanini M (1997). Infecção intra-uterina pelo vírus da leucose bovina. Rev. Bras. Reprod. Anim. 21(4):8-11.

  
 

Javier R, Butel J (2008). The History of Tumor Virology. Cancer Res. 68(19):7693-7706.
Crossref

  
 

Kamihira S, Sugahara K, Tsuruda K, Uemura A, Akamatsu N, Nagai H, Murata K, Hasegawa, Hirakata Y, Takasaki Y, Tsukasaki K, Yamada K (2005). Proviral status of HTLV-1 integrated into the host genomic DNA of adult T-cell leukemia cells. Clin. Lab. Haematol. 27:235-241.
Crossref

  
 

Kashanchi F, Brady JN (2005). Transcriptional and post-transcriptional gene regulation of HTLV-1. Oncogene 24:5938-5951.
Crossref

  
 

Katoh I, Yoshinaka Y, Ikawa Y (1989). Bovine leukemia virus trans-activator p38 tax activates heterologous promoters with a commons equence known as a cAMP-responsive element or the binding site of a celular transcription factor ATF. EMBO J. 8:497-503.

  
 

Kettmann R, Deschamps J, Cleuter Y, Couez D, Burny A, Marbaix G (1982). Leukemogenesis by bovine leukemia virus: proviral DNA integration and lack of RNA expression of viral long terminal repeat and 3' proximate celular sequences. Proc. Natl. Acad. Sci. 79:2465-2469.
Crossref

  
 

Klener P, Szynal M, Cleuter Y, Merimi M, Duvillier H, Lallemand F, Bagnis C, Griebel P, Sotiriou C, Burny A, Martiat P,Van der Broeke A (2006). Insights into Genes Expression Changes Impacting B-Cell Transfor- mation: Cross-Species Microarray Analysis of Bovine Leukemia Virus Tax-Responsive Genes in Ovine B Cells. J. Virol. 80(4):1922-1938.
Crossref

  
 

Lagarias DM, Radke K (1989). Transcriptional activation of bovine leukemia virus in blood cells from experimentally infected, asymptomatic sheep with latent infections. J. Virol. 63:2099-2107.

  
 

Lassauzet MLG, Thurmond MC, Johson WO, Holmberg CA. (1991). Factors Associated with in utero or periparturient transmission of Bovine Leukemia virus in calves on a California Dairy. Can. J. Vet. Res. 55:264-268.

  
 

Lee J, Kim Y, Kang C, Cho D, Shin D, Yum Y, Oh J, Kim S, Hwang M, Lim C, Yang K, Han K (2005). Investigation of the Bovine Leukemia Virus Proviral DNA in Human Leukemias and Lung cancers in Korea. J. Korean Med. Sci. 20:603-606.
Crossref

  
 

Lefebvre L, Vanderplasschen A, Ciminale V, Heremans H, Dangoisse O, Jauniaux JC, Zelnik V, Burny A, Kettmann R, Willems L (2002). Oncoviral bovine leukemia virus G4 and human T-cell leukemia virus type 1 p13(II) accessory proteins interact with farnesylpyrophosphate synthetase. J. Virol. 76:1400-1414.
Crossref

  
 

Leisering A (1871). Hypertrophy der Malpigischen Korperchen der Milz. Bericht uber das Veterinarwesen im Konigreich Sachsen. 16:15-16.

  
 

Martinez AM, Gama LT, Canon J, Ginja C, Delgado JV, Dunner S, Landi V, Martin-Burriel I, Penedo MCT, Rodellar C, Vega-Pla JL, Acosta A, Alvarez LA, Camacho E, Cortés O, Marques JR, Martínez R, Martínez RD, Melucci L, Martínez-Velázquez G, Mu-oz JE, Postiglioni A, Quiroz J, Sponenberg P, Uffo O, Villalobos A, Zambrano D, Zaragoza P (2012). Genetic footprints of Iberian cattle in America 500 years after the arrival of Columbus. PLoS One 7(11):e49066.
Crossref

  
 

Mason AL, Gilady SY, Mackey JR (2011). Mouse Mammary Tumor Virus in Human Breast Cancer: Red Herring or Smoking Gun? Am. J. Pathol. 179(4):1588-1590.
Crossref

  
 

Matsuoka M, Jeang KT (2011). Human T-cell leukemia virus type 1 (HTLV- 1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy. Oncogene 30:1379-1389.
Crossref

  
 

Melana S, Picconi M, Rossi C, Mural J, Alonio L, Teyssie A, Holland J, Pogo B (2002). Detección de Secu- encias Homólogas al Gen env del Virus del Tumor Mamario Murino (MMTV) en Cáncer de Mama de Pacientes Argentinas. Medicina 62(4):323-327.

  
 

Merimi M, Klener P, Szynal M, Cleuter Y, Bagnis C, Kerkhofs P, Burny A, Martiat P, Van den Broeke A (2007). Complete suppression of viral gene expression is associated with the onset and progression of lymphoid malignancy: observations in Bovine Leukemia Virus-infected sheep. Retrovirology. 4:51.
Crossref

  
 

Mesa G, Ulloa C, Uribe M, Gutierrez M (2013). Bovine Leukemia Virus Gene Segment Detected in Human Breast Tissue. Open J. Med. Microbiol. 3(1):84-90.
Crossref

  
 

Miller JM, Miller LD, Olson C, Gillette KG (1969). Virus-like particles in phytohemagglutinin-stimulated lymphocyte cultures with reference to bovine lymphosarcoma. J. Natl. Cancer Inst. 43(6):1297-1305.

  
 

Murakami H, Yamada T, Suzuki M, Nakahara Y, Kazuhiko S, Sentsui H (2011). Bovine Leukemia Virus In- tegration Site Selection in Cattle That Develp Leukemia. Virus Res. 156(1-2):107-112.
Crossref

  
 

Nikbakht G, Rabbani M, Emam M, Rezatofighi E (2010). Serological and genomic detection of bovine leukemia virus in human and cattle samples. Int. J. Vet. 4:253-258.

  
 

Ochoa-Cruz A, Uribe A, Gutierrez M (2006). Zoonotic Behavior of the Bovine Leukemia Virus and Its Relationship with Breast Cancer, Univ. Sci. 11(2):31-40.

  
 

Oliver SP, Boor KJ, Murphy SC, Murinda SE (2009). Food Safety Hazards Associated with Consumption of Raw Milk. Foodborne Pathog. Dis. 6 (7):793-806.
Crossref

  
 

Olson C (1974). Bovine lymphosarcoma (leukemia) a synopsis. J. Am. Vet. Med. Assoc. 165 (7):630-632.

  
 

Olson C, Hoss HE, Miller JM, Baumgartener LE (1973). Evidence of bovine C-type (leukemia) virus in dairy cattle. J. Am. Vet. Med. Assoc. 163(4):355-357.

  
 

Pepper C, Hoy T, Bentley DP (1997). Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance. Br. J. Cancer 76:935-938.
Crossref

  
 

Rogers RJ, Dimmock CK, De vos A.J, Rodwell BJ (1988). Bovine leucosis virus contamination of a vaccine produced in vivo against bovine babesiosis and anaplasmosis. Aust. Vet. J. 65:285-287.
Crossref

  
 

Romero CH, Cruz GB, Rowe CA (1983). Transmission of bovine leukaemia virus in milk. Trop. Anim. Health Prod. 15:215-218.
Crossref

  
 

Sagata N, Yasunaga T, Ohishi K, Tsuzuku-Kawamura J, Onuma M, Ikawa Y (1984). Comparison of the entire genomes of bovine leukemia virus and Human T-cell leukemia virus and characterization of their unidentified open Reading frames. EMBO J. 3:3231-3237.

  
 

Schwartz I, Levy D. (1994) Pathobiology of bovine leukemia virus. Vet. Res. 25(6):521-536.

  
 

Sellers AT, Vierkant RA, Djeu A, Celis E, Wang AH, Kumar N, Cerhan NR (2008). Unpasteurized milk consumption and subsequent risk of cáncer. Cancer Causes Control 19(8):805-811.
Crossref

  
 

Slavikova K, Kettman R, Reinerová M, Zajac V, Portetelle D, Burny A (1987). Provirus integration of bovine leukemia virus into DNA of infected human myeloma cells. Neoplasma 34(6):653-657.

  
 

Tajima S, Aida Y (2005). Induction of expression of bovine leukemia virus (BLV) in blood taken from BLV-infected cows without removal of plasma. Microbes Infect. 7:1211-1216.
Crossref

  
 

Tajima S, Tsukamoto M, Aida Y. (2003) Latency of viral expression in vivo is not related to CpG methylation in the U3 region and part of the R región of the long terminal repeat of bovine leukemia virus. J. Virol. 77:4423-4430.
Crossref

  
 

Takahashi M, Tajima S, Okada K, Davis W, Aida Y (2005). Involvement of BLV Virus in Induction and Inhibition of Apoptosis. Microbes Infect. 7(1):19-28.
Crossref

  
 

Tanaka A, Takahashi C, Yamaoka S, Nosaka T, Maki M, Hatanaka M (1990). Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc. Natl. Acad. Sci. 87(3):1071-1075.
Crossref

  
 

Ursin G, Bjelke E, Heuch I, S.E. Vollset (1990). Milk consumption and cancer incidence: a Norwegian prospective study. Br. J. Cancer 61:454-459.
Crossref

  
 

Van Der Maaten JM, Miller JM, Schimerr MJF (1981). In útero transmission of bovine leukemia virus. Am. J. Vet. Research. 42(6):1052-1054.

  
 

Villalobos Cortes AI, Martinez AM, Escobar C, Vega-Pla JL, Delgado JV (2010) Study of genetic diversity of the Guaymi and Guabala bovine populations by means of microsatellites. Livest. Sci. 131:45-51.
Crossref

  
 

Villalobos Cortés AI, Gonzalez R (2015). A preliminary study of solute carrier family gene in adapted bovine breeds of Panama. Ital. J. Anim. Sci. 14:4057
Crossref

  
 

Weiss R, Teich N, Varmus, H, Coffin J (1985). RNA Tumor Viruses. New York: Cold Spring Harbor Laboratory. Pp. 504-522

  
 

Willems L, Gegonne A, Chen G, Burny A, Kettmann R, Ghysdael J (1987). The bovine leukemia virus p34 is a transactivator protein. EMBO J. 6:3385-3389.

  
 

Willems L, Kerkhofs P, Dequiedt F, Portetelle D, Mammerickx M, Burny A, Kettman (1994). Attenuation of bovine leukemia virus by deletion of R3 and G4 open reading frames. Proc. Natl. Acad. Sci. U.S.A. 91:11532–11536.
Crossref

  
 

Willems L, Grimonpont C, Kerkhofs P, Capiau C, Gheysen D, Conrath K, Roussef R, Mamoun R, Portetelle D, Burny A, Adam E (1998). Phosphorylation of bovine leukemia virus Tax protein is required for in vitro transformation but not for transactivation. Oncogene 16:2165-2176.
Crossref

  
 

Willems L, Heremans H, Chen G, Portetelle D, Billiau A, Burny A, Kettman R (1990). Cooperation between

  

 




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