This is the first renewal of a grant to investigate the mechanisms by which cyclin homologs encoded by ?-herpesviruses (v-cyclins) contribute to ?-herpesvirus pathogenesis and latency. The human ?-herpes viruses 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. We and others have been developing a small animal model system, infection of inbred mice with murine gammaherpesvirus 68 (yHV68), for analysis of the pathogenesis of ?-herpesvirus infection. This application focuses on the role of the ?HV68 v-cyclin in disease pathogenesis. Notably, the ?2-herpesviruses (HVS, KSHV and yHV68) all encode homologs of D-type cyclins, while EBV infection upregulates expression of host D-type cyclins. Thus, we expect analysis of the ?HV68 v-cyclin will provide important insights into a conserved pathogenic mechanism. We have shown that the ?HV68 v-cyclin is an oncogene that promotes cell cycle progression in primary lymphocytes and that a ?HV68 v-cyclin mutant reactivates inefficiently from latently infected M? and/or B cells (Progress Report). These observations lead to the following 4 aims.
Aim 1. Role of v-cyclin during chronic infection [assess impact of dose and route of infection on acute virus replication, latency and reactivation;in vivo infection competition analysis with wt and v-cyclin null yHV68;further characterize v-cyclin null yHV68 reactivation defect;characterization of chimeric virus harboring KSHV v-cyclin].
Aim 2. Transcriptional regulation of v-cyclin gene expression [role of lytic cycle-associated v-cyclin gene transcription;analysis of latency/reactivation-associated spliced v-cyclin gene transcripts;characterization of P1- and P2-initiated LANA/v-cyclin spliced transcripts].
Aim 3. Develop and characterize tissue culture models to investigate v-cyclin functions [CDK-dependent function during acute virus replication;CDK-independent function during virus reactivation from latency].
Aim 4. Characterize CDK-independent v-cyclin function [map domains required for virus reactivation;gene expression profiling comparing wt and CDK-binding mutant v-cyclin;identify and characterize cellular and viral proteins interacting with v-cyclin].

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-M (04))
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Daschner, Phillip J
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Emory University
Schools of Medicine
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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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