Control of HIV-1 infection in chronically infected patients has been revolutionized by highly active antiretroviral therapy (HAART). However, long term HAART is toxic and there is incomplete recovery of anti-HIV-1 T cell function;removal of HAART usually also results in rapid increases in viral load. Thus, we postulate that immunotherapy specifically directed to autologous virus can lead to adequate control of residual HIV-1 infection during HAART. We hypothesize that dendritic cells (DCs) loaded with apoptotic, autologous cells that are infected with autologous HIV-1 can serve as potent immunogens for activation of both CD8[+] and CD4[+] T cells specific for a broad range of autologous HIV-1 antigens. This is based on our recent findings that DCs loaded with HIV-1 infected, apoptotic cells induce CD8[+] and CD4[+] T cell responses specific for HIV-1 in vitro. To further refine this model, we propose to expand our preclinical studies by comparing the immunogenicity and the breadth of antigen specificity induced ex vivo by DCs loaded with apoptotic cells infected with autologous HIV-1 and DCs matured by different cytokine milieus. We will use this ex vivo model for determining the safety and immunogenicity of ex vivo loaded, autologous DCs as an HIV-1 immunogen in HIV-1 infected adults on HAART in a phase I clinical trial. Finally, we propose to monitor the breadth of CD8[+] and CD4[+] T cell responses to autologous HIV-1 and characterize viral evolutionary changes before and after ex vivo immunization. This DC-apoptotic cell model may be an ideal immunogen in that it contains all forms of HIV-1 proteins and can be used as a vehicle for therapeutic immunization with autologous virus.
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