This is a new RO1 grant proposal to investigate the mechanisms by which cyclin homologs encoded by gamma-Herpesviruses (v-cyclin) contribute to gamma-herpesvirus pathogenesis and latency. The human gamma-herpesviruses, KSHV and EBV, are important causes of cancer especially in immunocompromised individuals. Because of the species specificity of these viruses, in vivo studies of their pathogenesis have been limited. This proposal makes use of a small animal model system, infection of inbred mice with gammaHV68, for analysis of the pathogenesis of gamma-herpesvirus infection and the role of individual gamma-herpesvirus genes in latency and tumor induction. GammaHV68 infection is associated with the development of lymphoma and lymphoproliferative disease, severe vasculitis of the great elastic vessels and splenic fibrosis. Studies to date indicate the gammaHV68 shares pathogenetic mechanisms with EBV, KSHV, and HVS, validating it as a model for analysis of important questions in gammaherpesvirus pathogenesis. This grant is focused on the role of the gammaHV68 v-cyclin in disease pathogenesis. Notably, the gamma2- herpesviruses (HVS, KSHV and gammaHV68) all encode homologs of D-type cyclins, while EBV infection upregulates expression of host D-type cyclins. The investigators have shown that the gammaHV68 v-cyclin is an oncogene that promotes cell cycle progression in primary lymphocytes and that a gammaHV68 v-cyclin mutant reactivates inefficiently from latently infected Msigma and/or B cells. These observations lead to the following 3 specific aims of this proposal: 1) Determine the role(s) of the gammaHV68 v-cyclin in latency and reactivation. 2) Characterize regulation of gammaHV68 v-cyclin expression. 3) Determine the structural and biochemical basis of differences in the functions of the gammaHV68 v-cyclin and host D and E type cyclins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087650-03
Application #
6514680
Study Section
Special Emphasis Panel (ZRG1-AARR-4 (01))
Program Officer
Daschner, Phillip J
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$324,000
Indirect Cost
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Collins, Christopher M; Speck, Samuel H (2012) Tracking murine gammaherpesvirus 68 infection of germinal center B cells in vivo. PLoS One 7:e33230
Liang, Xiaozhen; Paden, Clinton R; Morales, Francine M et al. (2011) Murine gamma-herpesvirus immortalization of fetal liver-derived B cells requires both the viral cyclin D homolog and latency-associated nuclear antigen. PLoS Pathog 7:e1002220
Paden, Clinton R; Forrest, J Craig; Moorman, Nathaniel J et al. (2010) Murine gammaherpesvirus 68 LANA is essential for virus reactivation from splenocytes but not long-term carriage of viral genome. J Virol 84:7214-24
Gray, Kathleen S; Forrest, J Craig; Speck, Samuel H (2010) The de novo methyltransferases DNMT3a and DNMT3b target the murine gammaherpesvirus immediate-early gene 50 promoter during establishment of latency. J Virol 84:4946-59
Collins, Christopher M; Boss, Jeremy M; Speck, Samuel H (2009) Identification of infected B-cell populations by using a recombinant murine gammaherpesvirus 68 expressing a fluorescent protein. J Virol 83:6484-93
Herskowitz, Jeremy H; Siegel, Andrea M; Jacoby, Meagan A et al. (2008) Systematic mutagenesis of the murine gammaherpesvirus 68 M2 protein identifies domains important for chronic infection. J Virol 82:3295-310
Siegel, Andrea M; Herskowitz, Jeremy H; Speck, Samuel H (2008) The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation. PLoS Pathog 4:e1000039
DeZalia, Mark; Speck, Samuel H (2008) Identification of closely spaced but distinct transcription initiation sites for the murine gammaherpesvirus 68 latency-associated M2 gene. J Virol 82:7411-21
Gargano, Lisa M; Moser, Janice M; Speck, Samuel H (2008) Role for MyD88 signaling in murine gammaherpesvirus 68 latency. J Virol 82:3853-63
Evans, Andrew G; Moser, Janice M; Krug, Laurie T et al. (2008) A gammaherpesvirus-secreted activator of Vbeta4+ CD8+ T cells regulates chronic infection and immunopathology. J Exp Med 205:669-84

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