HIV-1-specific CD8+ T cells play an important role in controlling HIV-1 virus replication during acute infection. In contrast, the antiviral efficacy of HIV-1-specific CD8+ T cell responses during chronic infection is less apparent, and an increasing body of evidence indicates a functional impairment of these responses in chronic infection. However, very little is known about the precise factors leading to the impairment of antiviral activity of HIV-1-specific CD8+ T cell responses in chronic infection in humans. Data from persistent viral infections in the mouse model have demonstrated that both the deletion of virus-specific T cell clones as well as the functional impairment of persistent T cell responses, in particular in the absence of T help, contribute to the reduction of virus-specific immunity. Preliminary data presented in this proposal indicate that similar mechanisms can be observed in HIV-1 infected humans, and may lead to the alteration of HIV-1-specific CD8+ T cell function. To precisely determine the factors that lead to the impairment of an initially effective antiviral immune response, the PI proposes to study the evolution of HIV-1-specific CD8+ T cell function starting in acute HIV-1 infection in a unique cohort of subjects identified within the first weeks of HIV-1 infection, that has been characterized in detail for the specificity of their HIV-1-specific T cell responses during the initial funding cycle of this grant. Studies proposed in the first specific aim will characterize the clonotypic composition and function of the first wave of HIV-1-specific CD8+ T cell responses that are dominant in acute infection and their evolution over time. The second specific aim will investigate the impact of subsequent destruction of HIV-1-specific T cell help on HIV-1-specific CD8+ T cell function by comparing the function of """"""""helped"""""""" and """"""""helpless"""""""" CD8+ T cell populations. The third specific aim will build on these studies and test the potential of reconstituting HIV-1-specific CD8+ T cell function in chronic infection by selective reconstitution of T help using immunotherapeutic interventions. Taken together, the proposed studies, representing a direct extension of the work performed during the initial funding cycle, will provide crucial insights into our understanding of antiviral CD8+ T cell immunity in acute HIV-1 infection, the factors leading to the impairment of virus-specific CD8+ T cell function and the potentials for the reconstitution of CD8+ T cell function using immunotherapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050429-08
Application #
7603007
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2001-07-01
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
8
Fiscal Year
2009
Total Cost
$386,269
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Jost, Stephanie; Tomezsko, Phillip John; Rands, Keith et al. (2014) CD4+ T-cell help enhances NK cell function following therapeutic HIV-1 vaccination. J Virol 88:8349-54
Lichterfeld, Mathias; Gandhi, Rajesh T; Simmons, Rachel P et al. (2012) Induction of strong HIV-1-specific CD4+ T-cell responses using an HIV-1 gp120/NefTat vaccine adjuvanted with AS02A in antiretroviral-treated HIV-1-infected individuals. J Acquir Immune Defic Syndr 59:1-9
Streeck, Hendrik; Kwon, Douglas S; Pyo, Augustine et al. (2011) Epithelial adhesion molecules can inhibit HIV-1-specific CD8? T-cell functions. Blood 117:5112-22
Streeck, Hendrik; Jolin, Jonathan S; Qi, Ying et al. (2009) Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells. J Virol 83:7641-8
Brumme, Zabrina L; Brumme, Chanson J; Carlson, Jonathan et al. (2008) Marked epitope- and allele-specific differences in rates of mutation in human immunodeficiency type 1 (HIV-1) Gag, Pol, and Nef cytotoxic T-lymphocyte epitopes in acute/early HIV-1 infection. J Virol 82:9216-27
Streeck, Hendrik; Brumme, Zabrina L; Anastario, Michael et al. (2008) Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. PLoS Med 5:e100
Meier, Angela; Alter, Galit; Frahm, Nicole et al. (2007) MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol 81:8180-91
Streeck, Hendrik; Lichterfeld, Mathias; Alter, Galit et al. (2007) Recognition of a defined region within p24 gag by CD8+ T cells during primary human immunodeficiency virus type 1 infection in individuals expressing protective HLA class I alleles. J Virol 81:7725-31
Yu, X G; Lichterfeld, M; Addo, M M et al. (2005) Regulatory and accessory HIV-1 proteins: potential targets for HIV-1 vaccines? Curr Med Chem 12:741-7
Allen, Todd M; Yu, Xu G; Kalife, Elizabeth T et al. (2005) De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection. J Virol 79:12952-60

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