DENDRITIC CELL THERAPY FOR HIV--ROLE OF CYTOKINES ON ENHANCED T CELL FUNCTION

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Treatment of HIV-infected patients with highly active anti-retroviral therapy (HAART) regimens has led to marked reductions in HIV-1 viral load and improvements in peripheral CD4+ T cell counts. However, there is evidence that HAART alone may not result in complete return of normal lymphocyte number and function, and, in particular, HIV-specific immune function. We hypothesize that therapeutic immunization with autologous cultured DC, appropriately loaded with HIV antigens, will lead to the generation of a more effective cellular immune response to HIV-1 in the setting of effective anti-retroviral therapy. We propose to investigate the possibility that DC derived from HIV-infected patients on HAART have the potential to stimulate a strong, coordinate (CTL and Th) HIV-specific cellular response in vitro. This in vitro model will allow us to determine the feasibility of reconstituting HIV-specific immunity using DC administration following effective anti-retroviral therapy. In Aim 1 we will deliver HIV antigens to autologous cultured DC in order to stimulate and maintain HIV-specific T cell responses. In Aim 2 we will evaluate the impact of cytokines known to promote cell-mediated immunity on the magnitude and diversity of the antigen-specific T cell responses generated in vitro using antigen-primed DC. In Aim 3, we will investigate the effects of DC-T cell interactions on HIV-1 replication in vitro, and the role that cytokines play in regulating HIV replication in this setting. In Aim 4 we will perform clinical protocols to evaluate the safety and immunogenicity of autologous cultured DC, loaded with HIV and recall antigens, and in subsequent trials in combination with cytokines, administered to HIV-infect patients receiving HAART.