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 manipulate 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 (gHV68; 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. The proposed studies focus on the determining the function of one of the critical latency-associated antigens of gHV68, the M2 antigen.
Aim 1. In vivo characterization of gHV68 M2 mutant viruses, 1.a. Role of M2 antigen in the establishment of latency in specific B cell reservoirs; 1.b. Characterization of M2 mutant virus reactivation from B cells in response to a define stimulus; 1.c. Generation of M2-deficient mutants on a replication defective background; and 1.d. Adoptive transfer of gHV68 latently infected naive and memory B cells into uninfected recipient mice.
Aim 2. Characterization of gHV68 M2 B cell transgenic mice. 2.a. Generation and initial characterization of M2 B cell transgenic mice; and 2.b. Characterization of B cell development and responses in M2 B cell transgenic mice.
Aim 3. Identify and characterize interactions of the M2 antigen with cellular proteins. 3.a. Characterization of M2 antigen interaction with endophilin II and Grb2 in mammalian cells; 3.b. Generation and characterization of M2 mutant viruses that disrupt the interaction of M2 with endophilin II and/or Grb2; and 3.c. Characterization of the impact of M2 antigen expression on growth factor receptor and B cell receptor internalization and signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058057-05
Application #
7318879
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Beisel, Christopher E
Project Start
2003-12-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2009-11-30
Support Year
5
Fiscal Year
2008
Total Cost
$353,697
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
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Rangaswamy, Udaya S; O'Flaherty, Brigid M; Speck, Samuel H (2014) Tyrosine 129 of the murine gammaherpesvirus M2 protein is critical for M2 function in vivo. PLoS One 9:e105197
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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
Barton, Erik; Mandal, Pratyusha; Speck, Samuel H (2011) Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 29:351-97

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