Optimization Of HIV Specific Immune Responses In Vivo

成功研制艾滋病毒疫苗可能需要诱导抗体和/或细胞免疫反应，足以在感染后分别预防感染或疾病。虽然诱导多种其他传染性病原体的抗体反应很容易通过各种疫苗制剂实现，但减毒活疫苗、重组病毒疫苗或质粒DNA疫苗仅诱导诱导长期细胞免疫反应，特别是CD8+ T细胞反应。此外，由于HIV减毒活疫苗可能出于安全考虑而无法使用，而DNA疫苗目前在人体中仅能诱导适度的CD8+ T细胞反应，因此迫切需要开发方法来增强免疫后人类CD8+ T细胞反应的产生和维持。本研究的重点是如何优化在啮齿类动物和灵长类动物接种疫苗后CD8+ T细胞反应的大小和持续时间，使用各种疫苗配方。

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.