?-herpesviruses are closely associated with the development of lymphoproliferative disease and lymphomas, as well as other cancers. Notably, herpesviruses in general are able to establish life-long infections in their natural host(s). The long term goal of this research is to understand how ?-herpesviruses manipulate normal B or T cell development to persist within the lymphoid compartment of the infected host. Understanding the mechanisms used by ?- herpesviruses to persist in the infected host may lead to the development of strategies for interfering with chronic infection. Such therapies would be useful in the management of immunosuppressed individuals (e.g., organ transplant and AIDS patients) who are particularly susceptible to developing ?-herpesvirus-associated tumors. The focus of the proposed studies on murine ?-herpesvirus 68 (MHV68;also referred to as MHV68) represents an ongoing effort to develop a tractable small animal model for characterizing establishment and maintenance of ?-herpesvirus latency within the lymphoid compartment, and to determine the importance of B cell latency in the maintenance of chronic infection.
The specific aims of this renewal application are as follows:
Aim 1. Characterization of MHV68 immortalized murine fetal liver-derived B cell lines: 1.a. Identify stage of B cell differentiation of MHV68 infected FLC-derived B cell lines;1.b. Characterize viral gene expression in MHV68 infected FLC-derived B cell lines;1.c. Determine what viral genes are essential for FLC-derived B cell immortalization;and 1.d. Adoptive transfer of MHV68 infected FLC-derived B cell lines into immunocompetent mice.
Aim 2. Characterization of MHV68 latency programs and viral antigens: 2.a. Identify viral genes expressed in distinct latently infected B cell and macrophage populations; 2.b. Characterize alterations in target cells with viral mutants and altered routes of inoculation;and 2.c. Characterize newly identified latency-associated gene products.
Aim 3. Role of B cells in maintaining chronic MHV68 infection: 3.a. Determine whether MHV68 infects progenitor cells in the bone marrow; 3.b. Characterize latently infected cell types in B cell-deficient (MuMT) mice;and 3.c. Assess consequences of depleting B cells prior to or following MHV68 infection.

Public Health Relevance

?-herpesviruses are able to establish life-long infections in their natural host(s), and 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 ?-herpesviruses manipulate normal B or T cell development to persist within the lymphoid compartment of the infected host, as insights in shared mechanisms utilized by this family of viruses may lead to the development of strategies for interfering with chronic infection. In particular, such therapies would be useful in the management of immunosuppressed individuals (e.g., organ transplant and AIDS patients) who are particularly susceptible to developing ?-herpesvirus-associated tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095318-09
Application #
8403756
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Daschner, Phillip J
Project Start
2002-04-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
9
Fiscal Year
2013
Total Cost
$310,947
Indirect Cost
$110,336
Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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-Gonzalez, 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
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
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
Forrest, J Craig; Speck, Samuel H (2008) Establishment of B-cell lines latently infected with reactivation-competent murine gammaherpesvirus 68 provides evidence for viral alteration of a DNA damage-signaling cascade. J Virol 82:7688-99

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