A major scientific challenge in the development of an effective AIDS vaccine is the identification of clear correlates of immunoprotection. An important component in this search is a more through understanding of the interaction between the recombinant vector-based vaccine-induced CD4+ and CD8+ T cells responses. Our preliminary findings suggest that both the function and the phenotype of vaccine-induced CD4+ and CD8+ T cell responses undergo significant modification following infection. These modifications are more complex than what can be revealed through analysis of 1L2 and/or IFN-gamma production and proliferative capability of the total T cell populations. In the proposed studies, we hypothesize that the functional and proliferative capacity of CD8+ T cell functions are dependent upon the presence of poly-functional CD4+ T cell responses.
In Aim 1, we have powered our studies to determine how the functional profile of recombinant vector-based vaccine-induced CD8+ T cell responses (defined as the pattern of cytokine production, ability to degranulate, and capacity to suppress virus replication) will correlate with the poly-functional profile of vaccine-induced CD4+ T cell responses.
In Aim 2, we will determine how the proliferative capability of poly-functional antigen-specific CD8+ T cells is supported by the presence of poly-functional (IL2+IFN-gamma+TNF-alpha+) vaccine induced CD4+ T cell responses. Moreover, we hypothesize that vaccine-induced T cell responses are under the control of natural or antigen-specific regulatory CD4 and/or CD8 T cells that could selectively influence the functional profile of vaccine-induced antigen-specific CD4+ and CD8+ T cell subsets and their proliferative capacity.
In Aim 3, we will address the hypothesis that T cell responses with function and proliferative capability similar to those induced by vaccine regimens are present during the acute phase of infection and the level of circulating antigen plays a major role in determining their functional profile. We will also compare vaccine-induced T cell responses to those directed against CMV as a model of chronic viral infection. These studies will provide new information on the interaction of poly-functional vaccine-induced T cell responses, and how they could change following """"""""in vivo"""""""" HIV-1 infection in the presence of different levels of virus replication. Overall, these findings will shed new insights on the importance and fate of vaccine-induced T cell responses in controlling HIV-infection.
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