Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) resulting from the lytic infection of oligodendrocytes by the human polyomavirus, JC virus (PML was once considered a rare complication of middle-aged and elderly patients with lymphoprolifera diseases. In recent years, however, increasingly high incidence of PML in AIDS patients than those wit immunosuppressive disorders led us to believe that PML may also be regarded as a AIDS-associated disease. Lytic phase of JCV appears to be highly complex and remains elusive. A growing body of experimental evidence suggests that the regulation of JC viral gene expression and replication is not mediated solely by the presence absence of a particular transcription factor in a given cell. Rather delicate interactions among transcription or interactions between host and viral regulatory proteins appear to be important determining factors in respect. In support of this hypothesis, we have recently presented evidence of specific functional interactions between a cellular factor, YB-1, and JCV T-antigen and showed that both proteins play important roles in J expression. In addition, our most recent published and unpublished data indicate that JCV late Agno protein, antigen, also appears to have regulatory roles in both viral gene expression and DNA replication through interaction with viral and cellular proteins, notably with T-antigen and YB-1. Hence, here we propose investigate the molecular mechanisms involved in regulation of JCV by the functional interplay between T-antigen, Agno and YB-1. By employing molecular biology, genetics and virological approaches, we will i) perform thorough molecular virological studies to determine the role of Agno in regulation of JCV gene transcription and replication by examining its physical and functional interaction with T-antigen and YB- 1; ii) investigate the function importance of Agno viral lytic cycle by means of both ectopic expression of Agno early in infection mutational analysis and; iii) characterize the potential phosphorylation sites of Agno protein and investigate the role in JCV life cycle. The results from such comprehensive studies will provide valuable information underlying mechanisms involved in both JCV gene regulation and replication; and thereby the progression of JCV-induced CNS disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043108-05
Application #
7049334
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Wong, May
Project Start
2002-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$279,230
Indirect Cost
Name
Temple University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Saribas, A Sami; Mun, Sarah; Johnson, Jaslyn et al. (2014) Human polyoma JC virus minor capsid proteins, VP2 and VP3, enhance large T antigen binding to the origin of viral DNA replication: evidence for their involvement in regulation of the viral DNA replication. Virology 449:1-16
Coric, Pascale; Saribas, A Sami; Abou-Gharbia, Magid et al. (2014) Nuclear magnetic resonance structure revealed that the human polyomavirus JC virus agnoprotein contains an ?-helix encompassing the Leu/Ile/Phe-rich domain. J Virol 88:6556-75
Sami Saribas, A; Abou-Gharbia, Magid; Childers, Wayne et al. (2013) Essential roles of Leu/Ile/Phe-rich domain of JC virus agnoprotein in dimer/oligomer formation, protein stability and splicing of viral transcripts. Virology 443:161-76
Saribas, A Sami; White, Martyn K; Safak, Mahmut (2012) JC virus agnoprotein enhances large T antigen binding to the origin of viral DNA replication: evidence for its involvement in viral DNA replication. Virology 433:12-26
Sariyer, Ilker K; Saribas, Abdullah S; White, Martyn K et al. (2011) Infection by agnoprotein-negative mutants of polyomavirus JC and SV40 results in the release of virions that are mostly deficient in DNA content. Virol J 8:255
Saribas, A Sami; Arachea, Buenafe T; White, Martyn K et al. (2011) Human polyomavirus JC small regulatory agnoprotein forms highly stable dimers and oligomers: implications for their roles in agnoprotein function. Virology 420:51-65
Saribas, A Sami; Ozdemir, Ahmet; Lam, Cathy et al. (2010) JC virus-induced Progressive Multifocal Leukoencephalopathy. Future Virol 5:313-323
Staniszewska, Izabela; Sariyer, Ilker K; Lecht, Shimon et al. (2008) Integrin alpha9 beta1 is a receptor for nerve growth factor and other neurotrophins. J Cell Sci 121:504-13
Sariyer, Ilker K; Khalili, Kamel; Safak, Mahmut (2008) Dephosphorylation of JC virus agnoprotein by protein phosphatase 2A: inhibition by small t antigen. Virology 375:464-79
Khalili, Kamel; Sariyer, Ilker Kudret; Safak, Mahmut (2008) Small tumor antigen of polyomaviruses: role in viral life cycle and cell transformation. J Cell Physiol 215:309-19

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