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: 10618319
• 负责人: Rama Rao Amara
• 金额: $ 871.33万
• 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/10618319
• 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 envelope protein; 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; Productivity; 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; synergism; 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 埃默里非人类灵长类创新艾滋病疫苗和治疗研究联盟旨在 定义防止和根除 SHIV 感染的 B 和 T 细胞生物学机制。 联盟汇集了一系列跨学科、高度协作且富有成效的研究人员 HIV 疫苗和治疗学科的研究旨在解决以下总体假设：预防性疫苗的成功 我们在当前计划中开发的艾滋病毒疫苗是由于强大和持续的结合 全身和粘膜免疫反应由多功能抗体和组织驻留 CD8 组成。 T 细胞免疫，在遇到同源抗原时通过传统的溶细胞机制做出反应 并通过调节粘膜环境，使响应的 HIV 特异性 CD4+ T 细胞产生耐药性 此外，我们假设这种有效且平衡的疫苗反应将在以下情况下发生： 活性潜伏期逆转剂，减少病毒储存库，从而维持对病毒复制的抑制 停止高效抗逆转录病毒治疗后。 焦点 1 中的方法旨在了解疫苗保护机制，将利用 艺术技术和分析，以充分表征和利用组织驻留 CD8 T 的新群体 由我们的编码 Gag 作为免疫原的异源病毒载体疫苗（HVV 疫苗）诱导的细胞 与我们的 HIV 三聚体疫苗（蛋白质 疫苗）与新型佐剂共同提供，以提供针对异源 SHIV 挑战的长期保护 即使在没有强烈的中和抗体反应的情况下，我们也会在以后的几年中使用这种新颖的， 在 FOCUS 2 中，我们将追求优化疫苗并使其更接近临床研究的机制信息。 在感染 SHIV 并接受 ART 治疗的猕猴中，采用“电击和杀死”方法诱导潜伏病毒表达 在治疗性疫苗接种后使用潜伏期逆转剂（LRAs）感染细胞以增强病毒- 首先，能够清除病毒产生已被重新激活的 CD4 T 细胞的特异性免疫反应。 确定 HVV+蛋白疫苗在 ART 抑制的猕猴中的表现，然后研究其能力 在活跃的LRA的背景下耗尽储存库及其对控制病毒反弹的影响。 这些实验方法将得到有效的运营和管理支持的支持 组成部分和三个最先进的集中研究资源，以充分描述其规模， 单细胞分析和转录组学的功能、特异性和全部。 支持细胞水平上先天和适应性信号的表征。