The human gammaherpesviruses, Epstein-Barr virus and Human Herpesvirus-8, pose significant health problems in immunosuppressed individuals such as AIDS patients. Immune surveillance by antiviral T cells normally contains infected cells, however when this immune surveillance fails virus-transformed cells can outgrow and cause disease. The CD8 T cell response to gammaherpesviruses is relatively well characterized, but there is a growing appreciation that the CD4 T cell response may also play an important role in immune surveillance. However, a detailed dissection of the function and in vivo activity of gammaherpesvirus-specific CD4 T cells is not possible in human systems. Therefore we turned to a highly tractable mouse model, murine gammaherpesvirus-68, to address important questions regarding the CD4 T cell response. One significant problem which hinders the detailed study of CD4 T cell responses is that they are present at a very low frequency. Here we avoid this problem by using a system where the frequency of CD4 T cells is enlarged prior to infection, using T cell receptor transgenic CD4 T cells and recombinant MHV-68 containing the appropriate antigen. This system can then be used to track the virus-specific CD4 T cell response as the infection progresses.
In Specific Aim 1 we will use this system to determine the functional and phenotypic characteristics of the CD4 T cell response in MHV-68 infection. In addition we will determine the factors necessary for sustaining the CD4 T cell response so that it can endure long-term.
In Specific Aim 2 we will focus on another important role of the CD4 T cell response - licensing of dendritic cells. This CD40-dependent process is necessary for the transmission of CD4 T cell 'help'to the CD8 T cell response. In this aim we will determine how the biology of dendritic cells changes in the presence or absence of CD40, to understand licensing during MHV-68 infection on a molecular level. Our third Specific Aim focuses on the mechanism behind the loss of control of MHV-68 infection in mice deficient in T cell help. Our preliminary data detail a method of re-establishing control of MHV-68 infection in CD40-deficient mice, where the virus spontaneously reactivates in the lungs. Therefore this section proposes to understand the precise mechanism behind this effect, which may have important therapeutic benefit in AIDS patients suffering from disease caused by recurrent gammaherpesvirus infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069943-04
Application #
7866468
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Beisel, Christopher E
Project Start
2007-06-15
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$349,410
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
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
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
Allie, S Rameeza; Zhang, Weijun; Fuse, Shinchiro et al. (2011) Programmed death 1 regulates development of central memory CD8 T cells after acute viral infection. J Immunol 186:6280-6
Molloy, Michael J; Zhang, Weijun; Usherwood, Edward J (2011) Suppressive CD8+ T cells arise in the absence of CD4 help and compromise control of persistent virus. J Immunol 186:6218-26

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