Genes for Induction of T Cell Responses

诱导 T 细胞反应的基因

• 批准号: 7756631
• 负责人: FENG GAO
• 金额: $ 45.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7756631
• 关键词: AIDS Vaccines; Acute; Amino Acid Sequence; Antibodies; Antigens; Binding; Cells; Chronic; Consensus; DNA; Development; Epitopes; Gagging; Generations; Genes; Genetic; Genetic Variation; Grant; HIV Infections; HIV-1; HIV-1 vaccine; Immune response; Lead; Macaca mulatta; Mouse Strains; Mus; Principal Investigator; Screening procedure; T-Lymphocyte; Testing; Update; Vaccine Design; Vaccines; Vaccinia virus; Virus; Virus Diseases; clinical efficacy; comparative; design; env Genes; fusion gene; gene induction; immunogenicity; neutralizing antibody; nonhuman primate; novel; programs; response

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.

全球循环的HIV-1菌株之间的非凡遗传多样性构成了强大的 HIV-1疫苗设计的挑战。因此，迫切需要急需诱导广泛反应性和有效的T细胞免疫反应的AIDS疫苗。在最近的研究中，我们已经产生了所有HIV-1亚型的两个合成组M共有ENV基因（CON6和CON6）。组M共有圈序列与任何亚型ENV序列之间的遗传距离仅是彼此中亚型ENV序列中的一半（15％vs. 30％）。我们的初步结果表明，CON6和CON-S均具有生物学功能，保留的关键抗体结合表位，最重要的是，在三种小鼠菌株中诱导的T细胞反应比单个子类型ENK免疫具有更交叉反应，并且在宽度上与宽度A，B subtype a，B和C Envelent a，b和c Envypolent Immunect。项目3将使用DMA Prime成熟的疫苗病毒促进筛查策略来测试小鼠中集中式HIV-1基因诱导的T细胞免疫反应，并全面评估用于诱导有效的交叉反应抗HIV-HIV-1 T细胞反应的HIV-1疫苗的基因基因方法。我们将：1）确定诱导广泛的交叉反应T细胞反应的最佳共识ENV免疫原子，2）确定哪些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组共有的GAG-POL-NEF融合基因免疫原能否诱导 比当代亚型（A，B和C）GAG-POL-NEF融合基因免疫原子和4）研究较宽的T细胞免疫反应，以及4）研究亚型的急性感染病毒和其他来自项目1的新世代集中基因的亚型共识ENV免疫原子，以鉴定出最佳的免疫原性，以鉴定出诱导广泛反应性T细胞的最佳免疫力。诱导最佳T细胞反应的免疫原子将在项目4的非人类灵长类动物中进行评估。