Genes for Induction of T Cell Responses

全球传播的HIV-1病毒株之间非凡的遗传多样性构成了一个巨大的挑战。 HIV-1疫苗设计的挑战因此，迫切需要能够诱导广泛反应性和有效的T细胞免疫应答的艾滋病疫苗。在我们最近的研究中，我们已经产生了两个合成的M组共有env基因（CON 6和CON-S）的所有HIV-1亚型。M组共有env序列与任何亚型env序列之间的遗传距离仅为亚型env序列之间的遗传距离的一半（15%对30%）。我们的初步结果表明，CON 6和CON-S都具有生物学功能，保留了关键的抗体结合表位，最重要的是，在三种小鼠品系中诱导T细胞应答，其比单一亚型env免疫原更具交叉反应性，并且在广度上与亚型A、B和C env多价免疫原相似。项目3将使用DMA引发-重组牛痘病毒加强筛选策略在小鼠中测试由一系列集中的HIV-1基因诱导的T细胞免疫应答，并全面评估用于开发HIV-1免疫原的集中基因方法，这些免疫原诱导有效的交叉反应性抗HIV-1 T细胞应答。我们将：1）鉴定诱导广泛交叉反应性T细胞应答的最佳共有env免疫原，2）确定哪种集中免疫原设计可以诱导最广泛的T细胞免疫应答 在小鼠中，3）确定M组共有gag-pol-nef融合基因免疫原是否可以诱导 比当代亚型（A、B和C）gag-pol-nef融合基因免疫原更广泛的T细胞免疫应答，和4）研究来自急性感染病毒的亚型共有env免疫原和来自项目1的其他更新代集中基因，以鉴定用于诱导广泛反应性T细胞应答的最佳免疫原。在项目4中，将在非人灵长类动物中评价诱导最佳T细胞应答的免疫原。

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.