Supplement to Mechanisms of Protection in Live-attenuated AIDS Vaccines

这些最新研究的一个关键发现是，在SIV挑战之后，记忆SIV特异性 SIV免疫猕猴的CD8+T细胞反应仅限于阴道粘膜 在SIV挑战后，免疫激活程度很低。重要的是， 新城疫病毒免疫动物(100-500只SIVgag特异性T细胞)阴道内CD8+T细胞反应 细胞/10^CD3+T细胞)并不明显高于HIV患者PBMC中诱导的T细胞反应 疫苗临床试验参与者由众多候选艾滋病毒疫苗组成。因此，很难解释。 仅基于Shiv诱导的CD8+T细胞的强度在该模型中的一致性保护 回应。显然，CD8+T反应在阴道粘膜中的解剖位置可能是 对SHV介导的保护的解释，但这似乎不足以解释 在模型中观察到的一致保护。从免疫分析中的一个引人注目的观察 SHIV免疫动物的组织反应是有相对静止的环境 在生殖道粘膜中，CD8+T细胞与病毒相遇。事实上，我们发现，在 与未免疫的对照动物相比，Treg细胞和相关的调控基因升高 并在SIV后3-14天内维持在SIV免疫动物的阴道粘膜中 挑战。我们现在认为，阴道粘膜中适度的CD8+T细胞反应和 在这个模型中，阴道粘膜中的最低限度的免疫激活是保护所必需的。 系统。因此，在这个项目中，我们将直接和间接地测试生成的假设 由于最初的资助期。最后，我们打算确定SHIV免疫接种的程度 可以保护患有生殖道炎症的动物免受阴道SIV的影响 挑战，并确定SHIV免疫是否可以诱导对重复低剂量的保护 阴道和阴茎SIV暴露。后两个目标将现实地模拟艾滋病毒的状况 并对SHIV介导的保护的限度进行了严格的测试。

A key finding of these more recent stutdies is that, after SIV challenge, the anamnestic SIVspecific CD8+ T cells responses in SHIV-immunized monkeys were limited to the vaginal mucosa and there was minimal immune activation after the SIV challenge. Importantly, the magnitude of the CD8+ T cell responses in the vagina of SHIV-immunized animals (100-500 SIVgag-specific T cells/10^ CD3+ T cells) was not appreciably greater than T cell responses elicited in PBMC of HIV vaccine clinical trial participants by numerous candidate HIV vaccines. Thus it is difficult to explain the consistent protection in this model based only on the strength of the SHIV-elicited CD8+ T cells response. Clearly the anatomic location of the CD8+ T response in the vaginal mucosa may be an explanation for the SHIV-mediated protection, but that does not seem to be a sufficient to explain the consistent protection observed in the model. A striking observation from the analysis of immune responses in tissues of SHIV-immunized animals was that there is relatively quiescent environment in the genital tract mucosa in which the CD8+ T cells encounter the virus. In fact we found that, in contrast to unimmunized control animals, Treg cells and associated regulatory genes are elevated and maintained in the vaginal mucosa of SHIV-immunized animals within 3-14 days of SIV challenge. We now believe that both a modest CD8+ T cell response in the vaginal mucosa and minimal immune activation in the vaginal mucosa are NECESSARY for protection in this model system. Thus in this project, we will directly and indirectly test the hypothesis that was generated as a result of initial funding period. Finally, we intend to determine the extent to which SHIVimmunization can protect animals with pre-existing genital tract inflammation from vaginal SIV challenge and to determine if SHIV-immunization can elicit protection against repeated low dose vaginal and penile SIV exposure. These latter 2 AIMS will realistically model the conditions of HIV transmission and provide a rigorous test of the limits of SHIV-mediated protection.