Optimization Of HIV Specific Immune Responses In Vivo

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Successful development of a vaccine against HIV will likely require the induction of both antibody and/or cellular immune responses sufficient to prevent infection or disease respectively following infectious challenge. While the induction of antibody responses for a variety of other infectious pathogens is readily achieved by a variety of vaccine formulations, live attenuated, recombinant viral vaccines or plasmid DNA vaccines only induce the induction of long-lived cellular immune responses, particularly CD8+ T cell responses. Moreover, since live attenuated HIV vaccines might be precluded from use due to safety concerns and DNA vaccines at present only induce modest CD8+ T cell responses in humans, there is an urgent need to develop ways to enhance the generation and maintenance of CD8+ T cell responses in humans in following immunization. This study focuses on how to optimize the magnitude and duration of CD8+ T cell responses following vaccination in rodents and primates using a variety of vaccine formulations. The data obtained over this past year have shown the following; 1. Prime-boost immunization with SIV Gag protein and TLR 3 or 7/8 ligands elicit potent T cell responses in non-human primates. Such responses were noted in both peripheral blood mononuclear cells and were much higher in the broncheoalveolar lavage. Upon boosting with rAd-5 SIV , CD8+ T cell responses were further enhanced. Animals were challenged with SIV Mac 251. These results show that a heterologous prime-boost immunization regimen using a protein and TLR ligand followed by rAd-5 induces potent T cell immunity. 2. Experiments in NHP have compared HIV Gag DNA versus HIV Gag protein+ Poly I:C as a prime prior to rAd-5 Gag as a boost. The data reveals that priming with DNA enhances both CD4 and CD8 responses after the rAd5 HIV Gag boost compared to rAd5 HIV Gag alone. By contrast, priming with HIV Gag protein+ Poly I:C enhanced the magnitude of CD4 responses following the rAd5 boost but not CD8 responses. Moreover, it was notable that DNA immunization but not protein + Poly I:C induced a small frequency of CD8 cells after the priming. Collectively these data suggest that priming for CD8+ T cells is critical if there is to be further expansion of such cells after the boost.