Abstract

Gammaherpesviruses are closely associated with the development of lympho-proliferative 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 gamma-herpesviruses manipulate normal B cell development to persist within the lymphoid compartment of the infected host. Understanding the mechanisms used by gamma-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 gamma-herpesvirus-associated tumors. The focus of the proposed studies on murine gamma- herpesvirus 68 (MHV68) represents an ongoing effort to exploit this tractable small animal model to determine mechanism involved in the establishment and maintenance of ?-herpesvirus latency within the lymphoid compartment.
The specific aims of this renewal application are as follows:
Aim 1. Role of IL-21 in MHV68 B cell latency Aim 2. Characterize the early steps in the establishment of MHV68 latency in B cells Aim 3. Characterize the specificity of MHV68 latently infected B cell population

Public Health Relevance

?-herpesviruses are closely associated with the development of lympho-proliferative disease and lymphomas, as well as other cancers. The long term goal of this research is to understand how ?- herpesviruses manipulate normal B 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095318-14
Application #
9513434
Study Section
Virology - B Study Section (VIRB)
Program Officer
Daschner, Phillip J
Project Start
2003-06-16
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Emory University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

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
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

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