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

预防和根除 SIV/SHIV 感染的 B 和 T 细胞生物学

• 批准号: 10462362
• 负责人: Rama Rao Amara
• 金额: $ 581.44万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462362
• 关键词: Address; Adjuvant; Animals; Antibodies; Antibody Formation; Antibody Response; Antigens; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular biology; Clinical Research; Discipline; Disease remission; Environment; Epigenetic Process; Gene Expression Profile; Goals; HIV; HIV resistance; HIV vaccine; HIV-1 vaccine; Highly Active Antiretroviral Therapy; Immune; Immune response; Immunity; Immunization; Immunomodulators; Individual; Infection; Interruption; Intravenous; Macaca; Macaca mulatta; Mediating; Mucosal Immune Responses; Mucous Membrane; Pathogenicity; Play; Population; Preventive vaccine; Production; Proteins; Refractory; Research; Research Personnel; Resistance; Resources; Role; SIV; Scheme; Serum; Shock; Signal Transduction; Specificity; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; Techniques; Tissues; Vaccinated; Vaccination; Vaccine Design; Vaccine Therapy; Vaccines; Viral Antigens; Viral Vector; Viral reservoir; Virus; Virus Diseases; Virus Replication; antigen challenge; antiretroviral therapy; delivery vehicle; innovation; latent HIV reservoir; neutralizing antibody; nonhuman primate; novel; operation; programs; prophylactic; response; simian human immunodeficiency virus; single cell analysis; success; therapeutic vaccine; transcriptomics; vaccine efficacy; vaccine response; vector; vector vaccine; viral rebound

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.

抽象的 Emory创新的HIV/AIDS疫苗的联盟和非人类灵长类动物的研究旨在 定义B和T细胞生物学的机制，可保护和根除SHIV感染。这 财团汇集了高度协作和产品调查人员的跨学科组合 艾滋病毒疫苗和治愈学科，以解决预防性成功的总体假设 我们在当前计划期间开发的HIV疫苗是由于强大而持续的 系统性和粘膜免疫反应。这是多功能抗体和组织居民CD8完成的 T细胞免疫，该免疫力通过常规的溶剂机制遇到同源抗原反应 并通过调节粘膜环境，使得响应的HIV特异性CD4+ T细胞具有抗性 感染。此外，我们假设在这种情况下，这种潜力和平衡的疫苗反应将在 主动潜伏期逆转剂，减少病毒储存剂，从而保持病毒复制的抑制 停止高度活跃的抗逆转录病毒疗法。 旨在了解疫苗保护机制的焦点1中的方法将利用 艺术技术和分析以充分表征和利用新的组织居民CD8 T 由我们的异源病毒载体疫苗（HVV疫苗）诱导的细胞，将GAG作为免疫原编码 有效地与我们的HIV包膜诱导的体液免疫反应协同触发疫苗（蛋白质 疫苗与新型调节器共同交付，可长期保护异源SHIV挑战 即使没有强烈的中和抗体反应。在后来的几年中，我们将使用这本小说 机械信息以优化疫苗并将其更接近临床研究。在焦点2中，我们将追求， 在经湿感染的艺术处理的猕猴中，“震惊与杀伤”方法可诱导潜在的病毒表达 治疗疫苗接种后，使用潜伏期反转药物（LRA）感染细胞，以增强病毒 - 特定的免疫调查可以清除已重新激活病毒的CD4 T细胞。首先，威尔 确定HVV+蛋白疫苗在ART中的表现如何抑制猕猴，然后研究其能力 在活跃的LRA及其对控制病毒反弹的控制的背景下，耗尽了储层。 这些实验方法将得到有效的操作和管理支持的支持 组件和三个最新状态集中研究资源，以充分表征大小 体液反应的功能，特异性和曲目。单细胞分析和转录组学也将 支持先天和适应性信号在细胞水平上的表征。