Bovine Leukemia Virus DNA in Human Breast Tissue - Volume 20, Number 5—May 2014 - Emerging Infectious Disease journal - CDC
Volume 20, Number 5—May 2014
Bovine Leukemia Virus DNA in Human Breast Tissue
Gertrude Case Buehring , Hua Min Shen, Hanne M. Jensen, K. Yeon Choi1, Dejun Sun, and Gerard Nuovo
Author affiliations: University of California, Berkeley, California, USA (G.C. Buehring, H.M. Shen, K.Y. Choi, D. Sun); University of California Davis Medical Center, Sacramento, California, USA (H.M. Jensen); Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA (G. Nuovo)
Bovine leukosis (B-cell leukemia/lymphoma), first described in 1871 in Lithuania, was believed to be an infectious disease because it spread through herds of cattle. In 1969, a virus isolated from cultured lymphocytes of cattle in an afflicted herd was identified as the agent of bovine leukosis (1). Since then, bovine leukemia virus (BLV) has been extensively investigated. It is a deltaretrovirus, closely related to human T-cell leukemia virus (HTLV) 1 (2), and has typical retroviral genome regions: LTR (long terminal repeat, promoter region); gag (group-specific antigen, capsid region); pol (polymerase, reverse transcription region, which synthesizes a DNA copy of the BLV RNA genome); and env (envelope). However, unlike other oncogenic retroviruses, deltaretroviruses have an additional region, tax (trans-activating region of the X gene), which has regulatory functions and is oncogenic to host cells. tax causes malignant transformation not through integration and insertional mutagenesis, as many retroviruses do, but by inhibition of DNA repair (base excision pathway) and trans-activating disruption of cellular growth control mechanisms (2).
BLV-infected cattle herds are found worldwide. In the United States, ≈38% of beef herds, 84% of all dairy herds, and 100% of large-scale dairy operation herds are infected (3,4). On average, clinical leukosis develops in <5% of these cattle, which are excluded from the market as a result (1), but BLV-infected lymphocytes are also found in the blood and milk of subclinically infected cows (2). Concerns that this virus might infect humans through exposure to food products from subclinically infected animals prompted 10 studies that used what were then (1975–1979) state-of-the-art immunologic methods to test serum samples from a collective total of 1,761 humans, including cancer patients, farm workers, and veterinarians (5). In these studies no antibodies against BLV were detected, prompting Burridge to conclude in his review article, “There is no epidemiological or serological evidence from human studies to indicate that BLV can infect man” (5).
The advent of immunoblotting, ≈100 times more sensitive than techniques of the 1970s (6), enabled the detection of antibodies reactive with recombinant purified BLV p24 capsid protein in serum samples from 39% of 257 self-selected human volunteers (7). This study could not determine whether the antibodies were a response to infection or merely to heat-inactivated BLV consumed in food products. However, injection of sheep with raw milk from BLV-positive cows stimulated antibody production, whereas injection with pasteurized control milk did not (8,9). The finding of antibodies to BLV in humans prompted us to investigate human tissues for evidence of infection with BLV by using liquid-phase PCR (L-PCR), sequencing, in situ PCR, and immunohistochemical (IHC) testing. We focused on breast tissue because, in cattle, BLV DNA and p24 were detected in mammary tissue, whereas only BLV DNA was detected in lymphocytes (10).