Polyomaviruses are a growing family of small DNA viruses with a narrow tropism for both the host species and the cell type in which they productively replicate. Species host range may be constrained by requirements for precise molecular interactions between the viral T antigen, host replication proteins, including DNA polymerase, and the viral origin of replication, which are required for viral DNA replication. Cell type specificity involves, at least in part, transcription factors that are necessary for viral gene expression and restricted in their tissue distribution. In the case of the human polyomaviruses, BK virus (BKV) replication occurs in the tubular epithelial cells of the kidney, causing nephropathy in kidney allograft recipients, while JC virus (JCV) replication occurs in the glial cells of the central nervous system, where it causes progressive multifocal leukoencephalopathy. Three new human polyomaviruses have recently been discovered: MCV was found in Merkel cell carcinoma samples, while Karolinska Institute Virus and Washington University Virus were isolated from the respiratory tract. We discuss control mechanisms for gene expression in primate polyomaviruses, including simian vacuolating virus 40, BKV, and JCV. These mechanisms include not only modulation of promoter activities by transcription factor binding but also enhancer rearrangements, restriction of DNA methylation, alternate early mRNA splicing, cis-acting elements in the late mRNA leader sequence, and the production of viral microRNA.Polyomaviruses comprise a family of small nonenveloped DNA tumor viruses which have small, circular, doublestranded DNA genomes, have been isolated from many species of mammals and birds, and are characterized by a very limited host range with respect to the species that they can productively infect (48). We will focus mainly on three primate viruses, simian vacuolating virus 40 (SV40), BK virus (BKV), and JC virus (JCV), not only because they have taught us important lessons about eukaryotic molecular biology but also because BKV and JCV cause important human diseases. SV40 was discovered almost 50 years ago (115) and was the first primate polyomavirus to be described. SV40 differs significantly from the previously discovered mouse polyoma virus (111) in that it does not possess a middle T antigen in the early region and it expresses an accessory regulatory protein, agnoprotein, which is encoded in the late region. The species of origin of SV40 is the rhesus macaque, and the virus was discovered as a contaminant in early batches of polio vaccine. While the polio vaccinations at that time likely infected many people, the prevalence of SV40 infections in humans today has been debated (36,122). In 1971, two bona fide human polyomaviruses were discovered. BKV, also known as polyomavirus BK, was first isolated by Gardner et al. (37) by culture in Vero cells from the urine of a patient receiving immunosuppressive therapy following kidney transplantation. BKV is widespread throughout the human population around...
