Human gammaherpesviruses are associated with significant disease, and these are particularly prevalent in AIDS patients. In these patients virus-transformed cells can grow uncontrolled into tumors such as non-Hodgkin's lymphoma, primary CNS lymphoma and Kaposi's sarcoma. Such diseases occur as a consequence of latent infection by the virus, and it is therefore critical to understand the immunological control during latency. We propose to investigate several aspects of the immune surveillance mechanism using a mouse gammaherpesvirus model. Specifically we will test the following hypotheses: (i) That lytic and latent antigen-specific CD8 T cells make different contributions to the control of gammaherpesvirus latency. We will reconstitute latently-infected immunodeficient mice with T cell lines specific for either latent or lytic virus antigens and determine which ones are able to maintain control of the virus. We will also determine the mechanism by which these cells to control the virus. (ii) That different effector/memory T cell population play different roles in the control of latent infection. Effector/memory T cells have been found to be heterogeneous with respect to surface markers, effector function and migration. One marker that partly defines these populations in is CD62L. We will examine the roles of CD62Lhi and CD62LIo cells during latent infection using an adoptive transfer system. (iii) That virus-specific CD8 T cells involved in immune surveillance are regulated in a different manner to conventional memory CD8 T cells. Our preliminary data indicates that, unlike conventional memory T cells, MHV-68-specific CD8 T cells do not require IL-15 for proliferative renewal. We will therefore determine what regulates these CD8 T cells during the latent infection, with specific focus on the cytokines involved and the role of regulatory CD4+CD25+ T cells. The work described in this proposal will provide essential information to the poorly understood process of immune surveillance in gammaherpesvirus infections. In addition some of this information may also lead to a greater understanding of immune surveillance to other chronic virus infections or tumor cells. This work will lead to better therapies to combat tumor-associated virus infections.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA103642-04
Application #
7224932
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$279,728
Indirect Cost
Name
Dartmouth College
Department
Physiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Hu, Zhuting; Molloy, Michael J; Usherwood, Edward J (2016) CD4(+) T-cell dependence of primary CD8(+) T-cell response against vaccinia virus depends upon route of infection and viral dose. Cell Mol Immunol 13:82-93
Hu, Zhuting; Blackman, Marcia A; Kaye, Kenneth M et al. (2015) Functional heterogeneity in the CD4+ T cell response to murine ?-herpesvirus 68. J Immunol 194:2746-56
Gui, Jingang; Hu, Zhuting; Tsai, Ching-Yi et al. (2015) MCL1 enhances the survival of CD8+ memory T Cells after viral infection. J Virol 89:2405-14
Hu, Zhuting; Usherwood, Edward J (2014) Immune escape of ?-herpesviruses from adaptive immunity. Rev Med Virol 24:365-78
Hu, Zhuting; Zhang, Weijun; Usherwood, Edward J (2013) Regulatory CD8+ T cells associated with erosion of immune surveillance in persistent virus infection suppress in vitro and have a reversible proliferative defect. J Immunol 191:312-22
Tsai, Ching-Yi; Allie, S Rameeza; Zhang, Weijun et al. (2013) MicroRNA miR-155 affects antiviral effector and effector Memory CD8 T cell differentiation. J Virol 87:2348-51
Liang, Xiaozhan; Crepeau, Rebecca L; Zhang, Weijun et al. (2013) CD4 and CD8 T cells directly recognize murine gammaherpesvirus 68-immortalized cells and prevent tumor outgrowth. J Virol 87:6051-4
Allie, S Rameeza; Zhang, Weijun; Tsai, Ching-Yi et al. (2013) Critical role for all-trans retinoic acid for optimal effector and effector memory CD8 T cell differentiation. J Immunol 190:2178-87
Habison, Aline C; Beauchemin, Chantal; Simas, J Pedro et al. (2012) Murine gammaherpesvirus 68 LANA acts on terminal repeat DNA to mediate episome persistence. J Virol 86:11863-76
Fuse, Shinichiro; Tsai, Ching-Yi; Rommereim, Leah M et al. (2011) Differential requirements for CD80/86-CD28 costimulation in primary and memory CD4 T cell responses to vaccinia virus. Cell Immunol 266:130-4

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