Merkel cell polyomavirus

Merkel cell polyomavirus (MCV or MCPyV) was first described in January 2008 in Pittsburgh, Pennsylvania. It was the first example of a human viral pathogen discovered using unbiased metagenomic next-generation sequencing with a technique called digital transcriptome subtraction. MCV is one of seven currently known human oncoviruses. It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. Approximately 80% of Merkel cell carcinoma (MCC) tumors have been found to be infected with MCV. Three years later, a team of researchers at the Dana-Farber Cancer Institute developed an antibody that detected MCV expression in 97% of MCC tumors. MCV appears to be a common—if not universal—infection of older children and adults. It is found in respiratory secretions suggesting that it may be transmitted by a respiratory route. But it also can be found shedding from healthy skin, and in gastrointestinal tract tissues and elsewhere, and so its precise mode of transmission remains unknown. Most MCV viruses found in MCC tumors, however, have at least two mutations that render the virus nontransmissible: 1) The virus is integrated into the host genome in a monoclonal fashion and 2) The viral T antigen has truncation mutations that leave the T antigen unable to initiate DNA replication needed to propagate the virus. Evidence that MCV is the cause for most MCC tumors comes from studies in which T antigen oncoproteins from the virus are inhibited. Knock down of these viral proteins causes cells from MCV-positive MCC tumors to die whereas there is no effect on cells from tumors that are uninfected with the virus. This indicates that MCV is necessary to maintain the virus-positive tumor cells. Further, clonal pattern of MCV insertions into MCC cell genomes indicates that the virus was present in the Merkel cell before it underwent cancerous transformation. The IARC has recently classified MCV as a class 2A carcinogen. Polyomaviruses are small (~5400 base pair), non-enveloped, double-stranded DNA viruses. MCV is the fifth polyomavirus that infects humans to be discovered. It belongs to the murine polyomavirus group, one of the three main clades of polyomaviruses. (The group is named for murine polyomavirus, the earliest virus of the group to be discovered, and does not imply that MCV is transmitted to humans from rodents.) Although it has been confused with the controversial SV40 virus in some blog postings, it is a completely distinct virus. MCV is genetically most closely related to the African green monkey lymphotropic polyomavirus (formerly known as African green monkey lymphotropic papovavirus), which is consistent with MCV coevolving with human primates. The prototype sequence of MCV has a 5387 base pair double-stranded DNA (dsDNA) genome and encodes characteristic polyomavirus genes from opposite strands including a large T antigen, a small T antigen (LT and sT, respectively, from early strand) and viral capsid proteins VP1 and VP2/3 genes (from late strand) . MCV T antigen has similar features to the T antigens of other polyomaviruses, which are known oncoproteins, and is expressed in human tumors. The T antigen is a spliced gene that forms multiple different proteins depending on the splicing pattern. Both large T and small T oncoproteins are probably needed to transform healthy cells into cancer cells, and they act by targeting tumor suppressor proteins, such as retinoblastoma protein. The LT antigen possesses a helicase motif needed for virus replication that is deleted in MCC tumors. Unlike for other polyomaviruses, MCV sT antigen transforms cells in vitro by activating cap-dependent translation. MCV also expresses a microRNA (miRNA) known as MCV-miR-M1 from its late strand which bears perfect complementarity to LT and has been shown to negatively regulate LT expression . In addition to its role in regulating MCV LT expression and DNA replication, MCV-miR-M1 has been shown to directly target and downregulate the expression of host cell immune related transcript SP100 and it's role in the establishment of long-term persistent infection has been demonstrated in vitro. Merkel cell carcinoma is a highly aggressive type of skin cancer that was first described by Cyril Toker in 1972 as 'trabecular tumor of the skin'. The cancer may derive from the microscopic Merkel cell nervous organ in the skin and viscera which is responsible for touch and pressure sensation. Based on its origin, the cancer cell type is called a neuroectodermal tumor. Although rare compared with other skin cancers, the incidence of Merkel cell carcinoma in the USA tripled between 1986 and 2001, to around 1400 cases per year. Merkel cell carcinoma is mainly seen in older individuals. It is known to occur at increased frequency in people with immunodeficiency, including transplant recipients and people with AIDS, and this association suggests the possibility that a virus or other infectious agent might be involved in causing the cancer. Kaposi's sarcoma and Burkitt's lymphoma are examples of tumors known to have a viral etiology that occur at increased frequency in immunosuppressed people. Other factors associated with the development of this cancer include exposure to ultraviolet light.