This is a competing renewal of an R01 grant to determine how gamma-herpesvirus replication is controlled, both during reactivation from latency as well as following virus entry into a permissive cell. Gamma-herpesviruses are associated with the development of lymphoproliferative disorders and lymphoma, particularly in immunosuppressed individuals. A detailed understanding of how virus replication is triggered is critical to understanding the biology of gamma-herpesvirus infections, and may identify possible targets for interfering with viral persistence in the host. In this renewal application we propose to investigate the regulation of murine gamma-herpesvirus;68 (MHV68) replication. MHV68 infection of mice provides a tractable small animal model system for characterizing the role of specific genes in viral pathogenesis and maintenance of chronic infection. Studies on control of MHV68 replication will focus on the following aims:
Aim 1 : Regulation of gene 50 expression Aim 1.a. Identify critical cis-elements and trans-acting factors regulating gene 50 transcription;and.
Aim 1. b. Determine role of proximal and distal gene 50 promoters in MHV68 reactivation and replication.
Aim 2 : Regulation of Rta function and early gene expression Aim 2.a. Determine role of orf49 gene product in Rta activation of target promoters in B cells and non-B cells;
Aim 2. b. Identify immediate-early MHV68 genes involved in virus reactivation from B cells;
and Aim 2. c. Characterize impact of BLIMP-1 and XBP-1 on viral gene expression in B cells.
Aim 3 : Role of mLANA in virus reactivation and replication.
Aim 3. a. Identify functional domains in mLANA that contribute to virus reactivation/replication;
Aim 3. b. Identify and characterize mLANA associated proteins;
and Aim 3. c. Assess whether functional domains in KSHV LANA and mLANA are interchangable.

Public Health Relevance

Gamma-herpesviruses are associated with the development of lymphoproliferative diseases, including lymphomas, as well as other cancers. Understanding how virus reactivation is regulated may identify novel targets for therapeutic intervention. This grant aims to study the regulation of entry into the gamma-herpesvirus replication cycle.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-R (04))
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Daschner, Phillip J
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Emory University
Schools of Medicine
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Wakeman, Brian S; Johnson, L Steven; Paden, Clinton R et al. (2014) Identification of alternative transcripts encoding the essential murine gammaherpesvirus lytic transactivator RTA. J Virol 88:5474-90
Reese, T A; Wakeman, B S; Choi, H S et al. (2014) Helminth infection reactivates latent ?-herpesvirus via cytokine competition at a viral promoter. Science 345:573-7
Gray, Kathleen S; Collins, Christopher M; Speck, Samuel H (2012) Characterization of omental immune aggregates during establishment of a latent gammaherpesvirus infection. PLoS One 7:e43196
Stahl, James A; Paden, Clinton R; Chavan, Shweta S et al. (2012) Amplification of JNK signaling is necessary to complete the murine gammaherpesvirus 68 lytic replication cycle. J Virol 86:13253-62
Paden, Clinton R; Forrest, J Craig; Tibbetts, Scott A et al. (2012) Unbiased mutagenesis of MHV68 LANA reveals a DNA-binding domain required for LANA function in vitro and in vivo. PLoS Pathog 8:e1002906
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
Siegel, Andrea M; Rangaswamy, Udaya Shankari; Napier, Ruth J et al. (2010) Blimp-1-dependent plasma cell differentiation is required for efficient maintenance of murine gammaherpesvirus latency and antiviral antibody responses. J Virol 84:674-85

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