SV40 was initially isolated from cultures of rhesus monkey kidney cells being used to propagate vaccine strains of poliovirus (Sweet and Hilleman, 1960). At the time of its isolation, several million individuals had received poliovirus vaccines contaminated with significant amounts of this oncogenic virus (Shah and Nathanson, 1976). Fortunately, epidemiologic studies do not show increased rates of cancer among the inoculated individuals (Shah, 2000). However, recent studies suggest that SV40 may in fact circulate in the human population. SV40 has been associated with the development of a number of human cancers, including mesothelioma, osteosarcoma, and choroid plexus papillomas (Barbanti-Brodano et al., 1998; Bergsagel et al., 1992; Carbone et al., 1994, 1996; Lednicky et al., 1995).
SV40 has been the most widely studied polyomavirus, and it has been used as a model system for understanding many aspects of eukaryotic molecular biology, including DNA replication, transcription, and mRNA splicing. SV40 is also the only polyomavirus for which a specific cell surface protein (MHC class I) has been identified as a virus receptor (Atwood and Norkin, 1989; Breau et al., 1992).
SV40 is unique among polyomaviruses as it does not interact with sialic acids and therefore lacks the ability to hemagglutinate red blood cells. Sialydase treatment of monkey kidney cells also has no effect on either SV40 binding or SV40 infection (Clayson and Compans, 1989). Similarly, treatment of monkey kidney cells with phospholipase C, phospholipase D, trypsin, chymotrypsin, endoglycosidase F, and glycopeptidase F does not inhibit SV40 binding (Clay-son and Compans, 1989). The binding of SV40 to monkey kidney cells is saturable and of high avidity. The number of SV40 receptors on cells has been calculated at 9 X 104 with a dissociation constant of 3.76 pM (Table 9.2) (Clayson and Compans, 1989).
The subsequent identification of MHC class I proteins as a principal component of the SV40 receptor came about from experiments designed to determine whether SV40 infection reduced cell surface MHC class I protein expression (Atwood, 1991). It was reasoned that such a mechanism may account for the ability of SV40 to persist in its natural host, the rhesus macaque (At-wood, 1991; Norkin, 1982). During the course of these studies SV40 binding to cells was found to specifically inhibit the subsequent binding of antibodies directed at MHC class I proteins. Conversely, anti-MHC class I antibodies blocked the binding of radiolabeled SV40 to cells and inhibited infection in a dose-dependent manner (Atwood and Norkin, 1989). Subsequent experiments demonstrated that reconstitution of class I protein expression in two separate class I null cell lines could rescue virus binding to these cells but could not rescue infection (Breau et al., 1992). This indicated that MHC class I proteins were necessary but not sufficient for SV40 infection of cells. This was confirmed by a series of studies demonstrating that the distribution and levels of MHC class I protein expression on numerous human cell types did not correlate with their susceptibility to infection (Basak et al., 1992). These data indicate that additional factors contribute to SV40 tropism. These additional factors may include transcription factors and the presence of a co-receptor.
Biochemical data also support a role for MHC class I proteins as cell surface receptors for SV40. For example, the ability of papain to cleave cell surface class I molecules correlates with its ability to inhibit SV40 binding to cells (Clayson and Compans, 1989; Wong et al., 1984). Conversely, MHC class I proteins are resistant to digestion with trypsin and chymotrypsin, and neither of these enzymes inhibits virus binding (Clayson and Compans, 1989; Wong et al., 1984).
The discovery of the SV40 receptor led others to investigate whether related polyomaviruses might also use MHC class I proteins as a receptor. Two poly-omaviruses were examined, PyV and JCV, neither of which was found to use MHC class I proteins as a receptor (Liu et al., 1998; Sanjuan et al., 1992).
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