BK virus, JC virus and simian virus 40 infection in humans, and association with human tumors

BK virus (BKV), JC virus (JCV) and Simian virus 40 (SV40) are polyomaviruses, highly homologous at the DNA and protein levels. While the human polyomaviruses BKV and JCV are ubiquitous in humans, SV40 is a simian virus which was introduced in the human population, between 1955 and 1963, by contaminated poliovaccines produced in SV40-infected monkey cells. Epidemiological evidence suggests that SV40 is now contagiously transmitted in the human population by horizontal infection, independently from the earlier contaminated poliovaccines. All three polyomaviruses transform rodent and human cells and are oncogenic in rodents. JCV induces tumors also in experimentally inoculated monkeys. Transformation and oncogenicity induced by BKV, JCV and SV40 are due to the two viral oncoproteins, the large T antigen -(Tag) and the small t antigen (tag), encoded in the early region of the viral genome. Both proteins display several functions. The large Tag acts mainly by blocking the functions of p53 and pRB family tumor suppressor proteins and by inducing in host cells chromosomal aberrations and instability. The principal effect of small tag is to bind the catalytic and regulatory subunits of the protein phophatase PP2A, thereby constitutively activating the -catenin pathway which drives cells into proliferation. All three polyomaviruses are associated with specific human tumor types which correspond to the tumors induced by experimental inoculation of the three viruses in rodents and to the neoplasms arising in mice transgenic for the polyomavirus early region gene directed by the native viral early promoter-enhancer. Human tumors associated with BKV, JCV and SV40 contain viral DNA, generally episomic, express viral RNA and are positive for large Tag by immunohistochemistry. The low copy number of viral genomes in human tumors suggests that polyomaviruses may transform human cells by a “hit and run” mechanism. An autocrine-paracrine effect, involving secretion of growth factors by cells expressing polyomavirus Tag, may be responsible for recruiting to proliferation Tag-negative cells in polyomavirus-associated human tumors.