Gammaherpesviruses are closely associated with the development of lymphoproliferative disease and lymphomas, as well as other cancers. The long-term goal of this research is to understand how gammaherpesviruses manipulates normal B or T cell development to persist within the lymphoid compartment of the infected host. Understanding the mechanisms used by gammaherpesviruses to persist in the infected host may lead to the development of strategies for interfering with chronic infection. The focus of the proposed studies on murine gammaherpesvirus 68 (gammaHV68; also referred to as MHV-68) represents an ongoing effort to develop a tractable small animal model for characterizing establishment and maintenance of gammaherpesvirus infection.
Aim 1. Analyze gammaHV68 latency in B cells in vivo. 1.a. Quantitate B cell and non-B cell latency in the spleen as a function of time after intraperitoneal and intranasal infection; and 1.b. Characterize the phenotype(s) of latently infected B cells;
Aim 2. Quantitate turnover and dynamics of gammaHV68 latency in vivo; 2.a. Generate and characterize replication-deficient oHV68 mutants to determine the half-life of latency reservoirs in vivo; 2.b. Analyze spread of B cell latency by adoptive transfer of splenocytes from naive and latently infected immunocompetent mice into Rag 1-deficient mice; and 2.c. Monitor virus trafficking through B cells using genetically-marked viruses.
Aim 3. Assess the requirement for B cell latency for long-term gammaHV68 infection. 3.a. Generate recombinant viruses harboring a conditionally expressed diphtheria toxin gene; 3.b. Analyze conditional diphtheria toxin expressing viruses in normal and tissue-specific Cre recombinase expressing mice; and 3.c. Generate and characterize mice that conditionally express cre recombinase activity - utilization with conditional diphtheria toxin expressing gammaHV68.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095318-03
Application #
6892311
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2003-06-16
Project End
2008-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$320,400
Indirect Cost
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Collins, Christopher M; Speck, Samuel H (2015) Interleukin 21 signaling in B cells is required for efficient establishment of murine gammaherpesvirus latency. PLoS Pathog 11:e1004831
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
Collins, Christopher M; Speck, Samuel H (2014) Expansion of murine gammaherpesvirus latently infected B cells requires T follicular help. PLoS Pathog 10:e1004106
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
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
Krug, Laurie T; Torres-González, Edilson; Qin, Qianhong et al. (2010) Inhibition of NF-kappaB signaling reduces virus load and gammaherpesvirus-induced pulmonary fibrosis. Am J Pathol 177:608-21
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
Krug, Laurie T; Collins, Christopher M; Gargano, Lisa M et al. (2009) NF-kappaB p50 plays distinct roles in the establishment and control of murine gammaherpesvirus 68 latency. J Virol 83:4732-48

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