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.

摘要 埃默里非人灵长类动物创新艾滋病毒/艾滋病疫苗和治疗研究联盟旨在 明确B和T细胞生物学保护和根除SHIV感染的机制。的 联盟汇集了高度协作的跨学科组合，在一系列富有成效的调查人员 艾滋病毒疫苗和治疗学科，以解决总体假设，即成功的预防， 我们在目前的计划中开发的艾滋病毒疫苗是由于一个强大的和持续的组合， 全身和粘膜免疫应答。这是由多功能抗体和组织驻留CD 8 T细胞免疫，其在遇到同源抗原时通过常规细胞溶解机制应答 并通过调节粘膜环境，使得应答HIV特异性CD 4 + T细胞具有抗性， 感染此外，我们假设，这种有效和平衡的疫苗反应将在 活性潜伏期逆转剂，减少病毒储库，从而维持对病毒复制的抑制 在停止高活性抗逆转录病毒治疗后。 FOCUS 1中的方法旨在了解疫苗保护机制，将利用 充分表征和利用新的组织驻留CD 8 T细胞群的现有技术和分析 由我们的编码Gag作为免疫原的异源性病毒载体疫苗（HVV疫苗）诱导的细胞， 有效地协同由我们的HIV包膜三聚体疫苗（蛋白质）诱导的体液免疫应答 疫苗）与新型佐剂共同递送以提供针对异源SHIV攻击的长期保护 即使在没有强中和抗体应答的情况下。在以后的岁月里，我们将用这本小说， 机制信息，以优化疫苗，使其更接近临床研究。在焦点2中，我们将继续， 在SHIV感染的ART治疗的猕猴中，“休克和杀死”方法诱导病毒从潜伏期表达， 在治疗性疫苗接种后使用潜伏期逆转剂（LRA）感染的细胞，旨在加强病毒- 特异性免疫应答能够清除其中病毒生产已被重新激活的CD 4 T细胞。第一，威尔 确定HVV+蛋白疫苗在ART抑制猕猴中的行为，然后研究其 在LRA活跃的情况下耗尽储存库及其对控制病毒反弹的影响。 这些试验性的方法将得到有效的业务和管理支助的支持。 组件和三个最先进的集中研究资源，以充分表征的幅度， 体液反应的功能、特异性和所有功能。单细胞分析和转录组学也将 支持在细胞水平上表征先天和适应性信号。