Small Tumor Antigen of Polyomaviruses: Role in Viral Life Cycle and Cell Transformation

Polyomaviruses are comprised of a family of non-enveloped DNA viruses with icosahedral capsids. Their genome is small, circular and double stranded and they are isolated from a variety of species, including humans, monkeys, rodents, and birds (Cole, 1996). Simian vacuolating virus 40 (SV40) and mouse polyomavirus were the first in the family to be discovered (Stewart et al., 1958; Sweet and Hilleman, 1960), both of which have provided a simple model system to study many aspects of DNA structure for more complex eukaryotic genomes (White and Khalili, 2004; White et al., 2005). In addition, their oncogenic proteins were also used as tools to discover and understand many signaling and transduction pathways (Pipas, 1992; Brodsky and Pipas, 1998; Sullivan and Pipas, 2002). During the early 1970s, two new members from humans were isolated, JC virus (JCV) and BK virus (BKV). JCV was isolated from the brain tissue of a patient suffering from progressive multifocal encephalopathy (PML) (Padgett et al., 1971). BKV was isolated from the urine of a kidney transplant patient with advanced renal failure (Gardner et al., 1971). Recently two new human members of polyomavirus were also discovered, one isolated from patient with symptoms of acute respiratory tract infection and named WU virus (Gaynor et al., 2007), the other was isolated from human respiratory tract samples by PCR amplification and named KI polyomavirus (Allander et al., 2007). JCV, SV40, and BKV are very closely related viruses because of their genomic organization and sequence similarity (White et al., 1992). Their genome is functionally divided into coding and noncoding regions (Cole, 1996). Coding regions can also be subdivided into early and late transcription units, early of which proceeds in a counter clockwise direction and encodes mainly regulatory proteins, including large T-Ag (LT-Ag), small t antigen (Sm t-Ag) (Major et al., 1992). The same region in JCV was also shown to encode alternatively spliced forms of LT-Ag, called T’ proteins (Bollag et al., 2006; Frisque et al., 2006). LT-Ag initiates viral DNA replication, transactivates late gene expression and plays a major role in cell transformation. The function of Sm t-Ag in these processes, however, is not clear although it was shown to play a major role in LT-Ag mediated cell transformation in SV40 (Bouck et al., 1978, 1984; Chang et al., 1984, 1985; Porras et al., 1996; Hahn et al., 2002; Zhao et al., 2003). T′ proteins was shown to differentially interact with pRb and play some roles in cell transformation (Bollag et al., 2006; Frisque et al., 2006). The late transcriptional unit encodes both regulatory (agnoprotein) and structural proteins (VP1, VP2, and VP3). Agnoprotein plays roles in viral replication, transcription (Safak et al., 2001, 2002) and virion biogenesis (Okada et al., 2005; Suzuki et al., 2005; Sariyer et al., 2006), whereas structural proteins are critical for viral attachment, penetration and delivery of viral DNA into the nucleus (Pho et al., 2000; Elphick et al., 2004; Daniels et al., 2006a,b). It was also recently discovered that SV40 late genome encodes a late protein, named VP4, whose synthesis initiates from a downstream start codon within the VP2 transcript. It appears that Vp4 mediates that the lysis of infected cells during the late phases of SV40 infection cycle (Daniels et al., 2007). Polyomaviruses exhibit tissue and species-specific tropism and this is mostly due to, at least in the case of JCV, BKV, and SV40, the unique structural organization of the regulatory region of each virus. For example, JCV and BKV exhibits tropism for oligodendrocytes and kidney epithelial cells respectively (Major et al., 1992; Hirsch and Steiger, 2003; Hirsch, 2005; Hirsch et al., 2006). The replication of JCV in CNS results in PML, which is characterized by the multiple foci formation at the demyelinated areas caused by lytic infection of oligodendrocytes (Major et al., 1992; Safak and Khalili, 2003) and PML develops in immunocomprimized individuals including AIDS patients (6–9, 130), although occurrence of PML was also reported in normal individuals (Berger, 2003; Berger and Houff, 2006). Reactivation of BKV, on the other hand, may result in polyomavirus-associated nephropathy (PVN), which develops in renal transplant patients and characterized by the formation of the viral inclusion bodies in the nuclei of kidney epithelial cells and that of interstitial nephritis (Hirsch and Steiger, 2003; Hirsch et al., 2006). The natural host for SV40 is the rhesus monkey and not the human, however, inadvertent exposure of human population due to a SV40 contaminated polyomavirus vaccination between 1955 and 1963 put SV40 into a spotlight and raised some concerns for public health. However, it should be pointed out here that SV40 poorly replicates in human cells (Cole, 1996). SV40, JCV, and BKV encode tumorogenic proteins including LT-Ag and Sm t-Ag. They have the potential to transform the cells in tissue culture and their tumorogenicity was demonstrated in experimental animals (London et al., 1978, 1983; Corallini et al., 1982; Miller et al., 1984; Butel, 1986; Small et al., 1986a,b; Butel et al., 1998, 1999; Butel and Lednicky, 1999; Gordon et al., 2000; Garcea, 2001). Their genomes were detected in a variety of human tumors (Corallini et al., 1987; Carbone et al., 1994, 1996; Krynska et al., 1999a) however it has yet to be conclusively determined whether they cause tumors in humans.