Cases are emerging which suggest that highly active anti-retroviral therapy [HAART] is not able to maintain complete antiviral potency with prolonged treatment. Recent evidence also indicates that significant, residual infection with latent HIV-1 DNA persists in long-lived CD4+ T cells, and can potentially be reactivated. We therefore propose that HAART is essential but insufficient for complete control of HIV-1 infection. Our hypothesis is that adequate control of HIV-1 infection in a significant portion of patients will require restoration of a broadly specific, highly active, anti-HIV-1 T cell immune responses. Moreover, recent evidences from our laboratories and others suggests that HAART results in significant restoration of CD4+ T helper cell function to non-HIV-1 recall antigens and mitogens, but is much less effective in recovering HIV-1 specific CD4+ and CD8+ T lymphocyte reactivity. In this program project we propose that engineering dendritic cells with HIV-1 and cytokine proteins or DNA will significantly augment anti-HIV-1 T cell reactivity either directly via in vivo administration, or through adoptive transfer after ex vivo processing of these antigenic forms. To fully explore the preclinical efficacy of this hypothesis, we will determine the effect of various forms of dendritic cell-based immunotherapy in the SIV/PMPA monkey model, which exhibits an antiviral effect similar to that of HAART regimens in HIV-1 infected humans. Parallel studies will define the capacity of engineered human dendritic cells to drive anti-HIV-1 T cell immunity in vitro, and will include a phase I trial of antigen and cytokine expressing dendritic cells in HIV-1 infected patients. This program project represents a convergence of strengths in HIV-1 basic and clinical research, newly established resources and expertise in SIV immunobiology and animal facilities, broad strengths in HIV-1 and IV T cell and dendritic cell research within several interactive laboratories, and exceptional resources in imaging and flow cytometry.
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