The long-term efficacy of combination antiretroviral therapy (ART) for control of human immunodeficiency virus 1 (HIV-1) infection may depend on augmentation of anti-HIV-1 CD8+ or CD4+ T cell responses. We have shown that combination ART does not result in sustained enhancement of anti-HIV-1 CD8+ or CD4+ T cell reactivity in HIV-1 infected patients with advanced immunodeficiency. However, there is still a substantial population of CD8+ T cells that bind HLA class I / HIV-1 peptide tetramers in these patients, and repetitive stimulations of peripheral blood mononuclear cells from HIV-1 positive and negative individuals with dendritic cells (DCs) loaded with liposome-complexed HIV-1 proteins can induce secondary and primary CD8+ T cell responses to HIV-1 antigens. We also found that HIV-1 sequence changes can identify the nature of evolutionary forces shaping the post-ART response as well as identifying potential candidates for modifying T-cell responses. We therefore hypothesize that there are functionally competent T cells specific for HIV-1 in ART patients that are strongly influenced by changes in HIV-1 epitope sequences recognized by T cells. Based on these findings, we have formed a team of experts in DC/ T cell immunology, flow cytometric phenotyping, HIV-1 biology and genetics, vector engineering, in vitro cell imaging and HLA typing to examine the boosting of anti-HIV-1 T cell responses by DCs.
In Aim #1 we propose to deliver HIV-1 proteins and whole virus bound to particulates, and apoptotic bodies derived from autologous CD4+ T cells infected with lab strain and autologous virus, and characterize various important aspects of their ability to present antigen to T cells. These DCs will be treated with cytokines, chemokines and anti-apoptotic agents to boost their T cell stimulatory abilities.
In aim #2, we will identify and characterize virus evolutionary changes prior to and following combination ART with emphasis on a near full spectrum of CD8+ T cell epitopes.
In aim #3, we will determine the fine-specificity and breadth of the T cell responses elicited by the engineered DCs based on antigen delivery systems developed in Aim #1 and the HIV-1 sequences derived in Aim#2. We believe that these new, novel antigen delivery systems and processing methods will be highly efficient at inducing a broad spectrum of anti-HIV-1 T cell responses in ART patients.
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