B and T Cell Biology of Protection from and Eradication of SIV/SHIV Infection

摘要 埃默里非人灵长类创新艾滋病毒/艾滋病疫苗和治疗研究联盟旨在 明确B和T细胞生物学预防和根除SHV感染的机制。这个 该联盟将高度协作和富有成效的调查人员的跨学科组合聚集在一起 HIV疫苗和治疗学科的研究，以解决预防措施成功的首要假设 我们在目前的项目中开发的HIV疫苗是由于强效和持久性的结合 全身和粘膜免疫反应。它由多功能抗体和组织驻留CD8组成 T细胞免疫，当遇到同源抗原时，它通过传统的细胞溶解机制做出反应 并通过调节粘膜环境，使应答的HIV特异性CD4+T细胞具有抵抗力 与感染有关。此外，我们假设，这种有效和平衡的疫苗反应将在以下背景下 活性潜伏期反转剂，减少病毒库，从而保持对病毒复制的抑制 在停止高效抗逆转录病毒治疗后。 重点1中的方法旨在了解疫苗保护的机制，将利用 充分刻画和利用组织常驻CD8T的新群体的技术和分析 编码Gag的异源病毒载体疫苗(HVV疫苗)诱导的细胞 与我们的HIV包膜三聚体疫苗(蛋白质)诱导的体液免疫反应有效协同 疫苗)与新型佐剂共同递送，以提供针对异源SIV挑战的长期保护 即使在没有强烈中和抗体反应的情况下也是如此。在以后的几年里，我们将使用这部小说， 机械信息，以优化疫苗，并使其更接近临床研究。在焦点2中，我们将继续追寻， 在感染SHV病毒的猕猴中，ART治疗后，“休克并杀死”的方法从潜伏期诱导病毒表达 在治疗性疫苗接种后使用潜伏期反转剂(LRA)感染的细胞，目的是增强病毒- 特定的免疫反应能够清除其中的病毒生产重新激活的CD4T细胞。第一，威尔 确定HVV+蛋白疫苗在ART抑制的猕猴中的作用，然后研究其能力 在活跃的LRA及其对控制病毒反弹的影响的背景下耗尽储存库。 这些试验性方法将得到有效的运营和管理支持 组成和三个最先进的集中研究资源以充分表征大小， 体液反应的功能、特异性和谱系。单细胞分析和转录学也将 支持在细胞水平上表征先天和自适应信号。

ABSTRACT The Emory Consortium for Innovative HIV/AIDS Vaccine and Cure Research in Nonhuman Primates aims to define the mechanisms of the B and T Cell Biology of Protection from and Eradication of SHIV Infection. The consortium brings together an interdisciplinary mix of highly collaborative, and productive investigators in a range of HIV vaccine and cure disciplines to address the overarching hypothesis that the success of the prophylactic HIV vaccine we have developed during the current program is due to a combination of a strong and sustained systemic and mucosal immune response. This is comprised of multi-functional antibody and tissue resident CD8 T cell immunity, which upon encountering cognate antigen responds through conventional cytolytic mechanisms and through modulation of the mucosal environment, such that responding HIV-specific CD4+ T cell are resistant to infection. Moreover, we postulate that such a potent and balanced vaccine response will, in the context of active latency reversing agents, reduce viral reservoirs and thus maintain suppression of virus replication following cessation of highly active antiretroviral therapy. The approaches in FOCUS 1, aimed at understanding the mechanisms of vaccine protection, will utilize state of the art techniques and analyses to fully characterize and harness a novel population of tissue resident CD8 T cells induced by our Heterologous Viral Vector vaccine (HVV vaccine) encoding Gag as an immunogen to effectively synergize with the humoral immune response induced by our HIV envelope trimer vaccine (Protein vaccine) co-delivered with novel adjuvants to provide long-term protection against heterologous SHIV challenge even in the absence of strong neutralizing antibody response. In the later years we will use this novel, mechanistic information to optimize the vaccine and move it closer to clinical studies. In FOCUS 2 we will pursue, in SHIV-infected ART-treated macaques, the “shock and kill” approach to induce virus expression from latently infected cells using latency reversal agents (LRAs) following therapeutic vaccination aimed at boosting virus- specific immune responses able to clear CD4 T cells in which virus production has been reactivated. First, will determine how the HVV+Protein vaccine behaves in ART suppressed macaques and then study its ability to deplete the reservoir in the context of active LRAs and its impact on control of viral rebound. These experimental approaches will be supported by an effective Operations and Management Support component and three state of the art Centralized Research Resources to fully characterize the magnitude, function, specificity and repertoire of the humoral response. Single cell analysis and transcriptomics will also support characterization of innate and adaptive signals at the cellular level.