A cornucopia of human polyomaviruses
ABSTRACT During the past 6 years, focused virus hunting has led to the discovery of nine new human polyomaviruses, including Merkel cell polyomavirus, which has been linked to Merkel cell carcinoma, a lethal skin cell cancer. The discovery of so many new and highly divergent human polyomaviruses raises key questions regarding their evolution, tropism, latency, reactivation, immune evasion and contribution to disease. This Review describes the similarities and differences among the new human polyomaviruses and discusses how these viruses might interact with their human host.
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ABSTRACT: Merkel cell carcinoma (MCC) is a rare and aggressive form of skin cancer. In at least 80% of all MCC, Merkel cell polyomavirus (MCPyV) DNA has undergone clonal integration into the host cell genome and most tumors express the MCPyV large and small T antigens. In all cases of MCC reported to date, the integrated MCPyV genome has undergone mutations in large T antigen. These mutations result in expression of a truncated large T antigen that retains the Rb binding or LXCXE motif but deletes the DNA binding and helicase domains. However, it is not known what are the transforming functions of full-length and truncated MCPyV large T antigen. We compared the transforming activities of full-length, truncated, as well as the alternatively spliced 57kT forms of MCPyV large T antigen. MCPyV large T antigen could bind to Rb but was unable to bind to p53. Furthermore, MCPyV truncated large T antigen was more effective than full-length and 57kT large T antigen in promoting the growth of human and mouse fibroblasts. In contrast, expression of the MCPyV large T antigen C-terminal 100 residues could inhibit the growth of several different cell types. These data imply that the deletion of the C-terminus of MCPyV large T antigen found in MCC serves not only to disrupt viral replication but also results in the loss of a distinct growth inhibitory function intrinsic to this region.Journal of Virology 03/2013; 87(11). DOI:10.1128/JVI.00385-13 · 4.65 Impact Factor
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ABSTRACT: This Review provides abstracts from a meeting held at the London School of Hygiene and Tropical Medicine, on April 11-12, 2013, to celebrate the legacy of John Snow. They describe conventional and unconventional applications of epidemiological methods to problems ranging from diarrhoeal disease, mental health, cancer, and accident care, to education, poverty, financial networks, crime, and violence. Common themes appear throughout, including recognition of the importance of Snow's example, the philosophical and practical implications of assessment of causality, and an emphasis on the evaluation of preventive, ameliorative, and curative interventions, in a wide variety of medical and societal examples. Almost all self-described epidemiologists nowadays work within the health arena, and this is the focus of most of the societies, journals, and courses that carry the name epidemiology. The range of applications evident in these contributions might encourage some of these institutions to consider broadening their remits. In so doing, they may contribute more directly to, and learn from, non-health-related areas that use the language and methods of epidemiology to address many important problems now facing the world.The Lancet 04/2013; 381(9874):1302-11. DOI:10.1016/S0140-6736(13)60771-0 · 45.22 Impact Factor
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ABSTRACT: Hundreds of virus-encoded microRNAs (miRNAs) have been uncovered, but an in depth functional understanding is lacking for most. A major challenge for the field is separating those miRNA targets that are biologically relevant from those that are not advantageous to the virus. Here we show that miRNAs from related variants of SV40 polyomavirus have differing host target repertoires (targetomes) while completely preserving their direct autoregulatory activity on virus-encoded early gene products. These results underscore the importance of miRNA-mediated viral gene autoregulation in some polyomavirus lifecycles. More broadly, these findings imply that some host targets of viral-encoded miRNAs are likely to be of little selective advantage to the virus and our approach provides a strategy for prioritizing relevant targets.Journal of Virology 08/2013; 87(20). DOI:10.1128/JVI.01711-13 · 4.65 Impact Factor