Genes for Induction of T Cell Responses

全球流行的HIV-1毒株之间的非凡遗传多样性构成了一个令人敬畏的 HIV-1疫苗设计的挑战。因此，迫切需要能够诱导广泛反应和有效的T细胞免疫反应的艾滋病疫苗。在我们最近的研究中，我们已经合成了两个针对所有HIV-1亚型的M组共识env基因(Con6和Con-S)。M组共有包膜序列和任何亚型包膜序列之间的遗传距离仅为亚型包膜序列之间的遗传距离的一半(15%比30%)。我们的初步结果表明，Con6和Con-S都具有生物学功能，保存了关键的抗体结合表位，最重要的是，它们在三个品系的小鼠中诱导了T细胞反应，它们比单一亚型包膜免疫原更具交叉反应，在广度上与A、B和C亚型包膜多价免疫原相似。项目3将使用DMA PRIME重组痘苗病毒Boost筛选策略测试一系列集中的HIV-1基因在小鼠中诱导的T细胞免疫反应，并全面评估用于开发可诱导强大的交叉反应抗HIV-1 T细胞反应的HIV-1免疫原的集中基因方法。我们将：1)确定诱导广泛交叉反应T细胞反应的最佳共识环境免疫原，2)确定哪种集中式免疫原设计可以诱导最广泛的T细胞免疫反应 在小鼠中，3)确定M组共识gag-polnef融合基因免疫原是否能诱导 与当代亚型(A、B和C)Gag-polnef融合基因免疫原相比，更广泛的T细胞免疫反应；4)研究来自急性感染病毒和项目1中其他新一代集中基因的亚型共识env免疫原，以确定诱导广泛反应的T细胞反应的最佳免疫原。在项目4中，诱导最佳T细胞反应的免疫原将在非人类灵长类动物中进行评估。

The extraordinary genetic diversity among globally circulating HIV-1 strains poses a formidable challenge for HIV-1 vaccine design. Therefore, AIDS vaccines that can induce broadly reactive and potent T cell immune responses are urgently needed. In our recent studies, we have generated two synthetic group M consensus env genes (CON6 and CON-S) of all HIV-1 subtypes. The genetic distance between the group M consensus env sequences and any subtype env sequences is only half of those among subtype env sequences to each other (15% vs. 30%). Our preliminary results have shown that both CON6 and CON-S were biologically functional, preserved key antibody binding epitopes and, most importantly, induced T cell responses in three strains of mice that were more cross-reactive than single subtype env immunogens, and were similar in breadth to a subtype A, B and C env polyvalent immunogen. Project 3 will test T cell immune responses induced by a spectrum of centralized HIV-1 genes in mice using a DMA prime-recombinant vaccinia virus boost screening strategy, and comprehensively evaluate the centralized gene approach for development of HIV-1 immunogens that induce potent cross-reactive anti-HIV-1 T cell responses. We will: 1) identify optimal consensus env immunogens that induce broad cross-reactive T cell responses, 2) determine which centralized immunogen designs can induce the broadest T cell immune responses in mice, 3) determine if the group M consensus gag-pol-nef fusion gene immunogens can induce broader T cell immune responses than contemporary subtype (A, B and C) gag-pol-nef fusion gene immunogens, and 4) study the subtype consensus env immunogens from acute infection viruses and other newer generations of centralized genes from Project 1 to identify optimal immunogens for inducing broadly reactive T cell responses. The immunogens that induce optimal T cell responses will be evaluated in non-human primates in Project 4.