The full, infectious viral life cycle of human PyVs has only been studied for JCPyV and BKPyV because no infectious system exists up to now for the other human PyVs (Fig. 5). As PyVs are non-enveloped viruses, the viral capsid proteins interact directly with the receptor molecules in order to gain entry into the cells, being this interaction a major determinant of host and tissue tropism. Entry of PyVs into the cells includes receptor binding, internalization and intracellular trafficking, virus uncoating and nuclear entry. Once the uncoated viral genome is inside the cells, the

regulatory early proteins [Large tumor antigen (LT-ag) learn more and small T antigen (sT-ag) are produced in all PyVs. Besides LT-ag and sT-ag, other virus-specific T-antigen isoforms [such as middle T antigen Nutlin-3 ic50 (mT-ag) in rodent PyVs, the 17kT antigen in SV40 and the 57kT antigen in Merkel cell polyomavirus (MCPyV)] are derived from alternative splicing of the LT-ag transcript (Cheng et al., 2009, An et al., 2012 and Topalis et al., 2013). Some PyVs can cause tumors and products from the early region, especially SV40 LT-ag and murine PyV mT-ag, are required for cellular transformation. In benign lesions induced by PyVs, viral genomes are typically maintained extra-chromosomally. Malignant progression, as in the case of Merkel

cell carcinoma (MCC), is associated with viral integration into host cell chromatin (Fig. 3B). Although MCPyV is very common, MCC is very infrequent, most probably because integration is not part of the MCPyV life cycle and is a rare

event. This Cell press integration event is involved in the initiation of the tumor, since MCPyV was found to be clonally integrated into a single site of the host genome, indicating that viral integration preceded tumor expansion (Feng et al., 2008 and DeCaprio and Garcea, 2013). Recently, an overprinting gene, expressed from an Alternate Frame of the Large T Open reading frame (ALTO) was identified in MCPyV (Carter et al., 2013). Although ALTO is expressed during replication of MCPyV genome it is not required for replication. Despite no sequence similarities with the rodent mT-Ag, ALTO was found to be evolutionary related to mT-ag. Both PyV and PVs multiply in the nucleus of the infected cell and their circular genome associates with host encoded histones in the virions. These small DNA tumor viruses widely rely on the host cell DNA replication machinery to replicate their genomes. The LT-ag in PyVs is a multifunctional initiator protein that can successively recognize the viral origin of replication, assemble into a double hexamer melting and unwinding the DNA ahead of the replication fork, and interact with the host DNA replication factors (such as polymerase α-primase, replication protein A (RPA) and topoisomerase I (Fig. 6A).