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 #
2R01AI050429-06A1
Application #
7276527
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
2007-05-15
Budget End
2008-04-30
Support Year
6
Fiscal Year
2007
Total Cost
$418,750
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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