Merkel cell carcinoma (MCC) is a highly aggressive form of skin cancer that typically affects older and/or immunosuppressed individuals. Although MCC is relatively rare, its incidence in the U.S. has increased dramatically in the past decade. In 2008, DNA from a previously-unidentified polyomavirus was found to be present in a substantial majority of MCC tumors. The result suggests the possibility that the virus may be an etiologic cause of MCC and perhaps other forms of cancer. In FY08, work in the Tumor Virus Molecular Biology Section was focused on the biology of the human papillomavirus (HPV) virion. In FY09 we succeeded in applying a variety of tools originally developed for HPV research to the study of the newly-discovered Merkel cell polyomavirus (MCV). As a result, our Section is well situated to rapidly answer several important questions about MCV biology. MCV-based reporter vectors are a primary technology for this project. Production of the MCV vectors relies on intracellular expression of the MCV capsid proteins, which are capable of packaging reporter plasmids of interest in the milieu of the cell nucleus. The MCV reporter vectors are capable of delivering the packaged reporter plasmid to cultured cells, likely via mechanisms that resemble the infectious entry pathway of authentic MCV.In FY10, we completed studies showing that the infectivity of MCV vectors can be inhibited by MCV-specific antibodies. This allowed us to develop a high-throughput assay for quantitative analysis of antibody responses elicited by natural infection with MCV. We found that a great majority of adults display MCV-specific antibody responses, suggesting that infection is very common. Although infection appears to be common, we found that the magnitude of normal adults'antibody responses to MCV was typically much lower than the MCV-specific antibody responses observed in MCC patients. The result suggests a model in which MCC patients have typically experienced an unusually immunogenic form of MCV infection. Extremely strong antibody responses against MCV might thus serve as a biomarker for MCV-associated diseases.A major focus of our work during FY10 was elucidation of the infectious entry pathways that MCV uses to gain entry into host cells. This work showed that MCV employs heparan sulfate as the same primary attachment factor. The result draws a surprising parallel with HPVs, which also use heparan sulfate for initial attachment to cells. The result could point the way toward development of topical microbicides that might inhibit MCV infection.Further work during FY10 revealed that apparently healthy human skin surfaces are often chronically infected with MCV, suggesting that this is the major reservoir of the virus. The work serendipitously revealed the existence of two additional skin-dwelling viruses, human polyomavirus 6 (HPyV6) and HPyV7. A major portion of the lab's work in FY11 will be aimed at discovering whether HPyV6 or HPyV7 are associated with human disease.During fiscal year 2011, our group discovered the cell-attachment receptor that MCV uses for infectious entry into host cells and shed light on an additional co-receptor moiety that plays a post-attachment role in the entry process. In collaboration with Thilo Stehle's lab, we elucidated the structure of the MCV capsid protein VP1 with a model co-receptor glycan.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011090-05
Application #
8552974
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$397,155
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Liu, Wei; Yang, Ruifeng; Payne, Aimee S et al. (2016) Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection. Cell Host Microbe 19:775-87
Gupta, Tushar; Robles, Maria Teresa Sáenz; Schowalter, Rachel M et al. (2016) Expression of the small T antigen of Lymphotropic Papovavirus is sufficient to transform primary mouse embryo fibroblasts. Virology 487:112-20
Buck, Christopher B; Van Doorslaer, Koenraad; Peretti, Alberto et al. (2016) The Ancient Evolutionary History of Polyomaviruses. PLoS Pathog 12:e1005574
Buck, Christopher B (2016) Exposing the Molecular Machinery of BK Polyomavirus. Structure 24:495
Tsang, Sabrina H; Wang, Ranran; Nakamaru-Ogiso, Eiko et al. (2016) The Oncogenic Small Tumor Antigen of Merkel Cell Polyomavirus Is an Iron-Sulfur Cluster Protein That Enhances Viral DNA Replication. J Virol 90:1544-56
Ray, Upasana; Cinque, Paola; Gerevini, Simonetta et al. (2015) JC polyomavirus mutants escape antibody-mediated neutralization. Sci Transl Med 7:306ra151
Ho, Jonhan; Jedrych, Jaroslaw J; Feng, Huichen et al. (2015) Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients. J Infect Dis 211:1560-5
Siebrasse, Erica A; Pastrana, Diana V; Nguyen, Nang L et al. (2015) WU polyomavirus in respiratory epithelial cells from lung transplant patient with Job syndrome. Emerg Infect Dis 21:103-6
Rennspiess, Dorit; Pujari, Sreedhar; Keijzers, Marlies et al. (2015) Detection of human polyomavirus 7 in human thymic epithelial tumors. J Thorac Oncol 10:360-6
Randhawa, P; Pastrana, D V; Zeng, G et al. (2015) Commercially available immunoglobulins contain virus neutralizing antibodies against all major genotypes of polyomavirus BK. Am J Transplant 15:1014-20

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