The long-term efficacy of combination anti-retroviral drug therapy (HAART) for control of human immunodeficiency virus 1 (HIV-1) infection appears to require augmentation of anti-HIV-1 CD8+ T cell responses using immunotherapeutic strategies. In the current phase of this R01 grant, we have shown that CD40L-matured dendritic cells (DCs) loaded with HIV-1 proteins, peptides or HIV-1 infected apoptotic cells, serve as potent immunogens for activation of memory and primary anti-HIV-1 CD8+ and CD4+ T cells. We hypothesize that the inherent naive repertoire of CD8+ T cells present prior to HIV-1 infection is sufficiently broad to recognize infecting viruses, as well as the variants of the CTL epitopes that evolve over the course of infection. Therefore, in Aim 1 we propose to test primary CD8+ T cell reactivity in samples obtained prior to infection for recognition of infecting, autologous viruses as well as variants of the epitopes recognized during early infection using autologous HIV-1 infected apoptotic bodies.
In Aim 2, we will characterize sequences of the infecting viruses and the later-evolving variants of epitopes recognized during early infection.
In Aim 3, we will assess the antigen processing mechanisms using DC live cell imaging and expression of markers involved in antigen processing pathways. Since the reconstitution of anti-HIV-1 responses following HAART has a number of similarities to the development of anti-HIV-1 responses following infection, characterization of pre-infection naive T cell responses will help formulate model strategies to enhance immune responses following HAART. We propose that this DC-apoptotic cell model may be an ideal immunogen that contains all antigenic forms of HIV-1 and can be a vehicle for therapeutic immunization.
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