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: 9117916
• 负责人: Rama Rao Amara
• 金额: $ 737.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117916
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Anti-Retroviral Agents; Antibodies; Antibody Diversity; Antibody Repertoire; Antibody Response; Antigens; B-Lymphocytes; Blood; Bone Marrow; CCR5 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cellular biology; Clinical Trials; Coupled; DNA; Data; Discipline; Epitopes; Equilibrium; Gene Expression; HIV; HIV vaccine; HIV-1 vaccine; Highly Active Antiretroviral Therapy; Image; Immune; Immune response; Immunity; Immunologic Adjuvants; Immunotherapy; Infection; Interruption; Location; Longevity; Lymphoid Tissue; Measures; Memory; Mucosal Immune Responses; Mucous Membrane; Nature; Neonatal; Pharmaceutical Preparations; Phase; Plasma Cells; Play; Population; Predisposition; Proteins; Reducing Agents; Regimen; Research; Research Personnel; Research Support; Role; SIV; Safety; Signal Transduction; Specificity; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; TLR7 gene; Tissues; Vaccination; Vaccines; Viral; Viral Vector; Viral reservoir; Virus; Virus Replication; Withdrawal; base; design; imprint; improved; innovation; nanoparticle; neutralizing antibody; nonhuman primate; novel; operation; programs; prophylactic; public health relevance; response; simian human immunodeficiency virus; therapeutic vaccine; transcriptomics; vaccine response; vector

 DESCRIPTION (provided by applicant): The Emory Consortium for Innovative AIDS Research in Nonhuman Primates aims to understand the B and T Cell Biology of Protection from and Eradication of SIV/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 a successful prophylactic HIV vaccine will require a strong and sustained systemic and mucosal immune response, comprised of functionally targeted antibody and tissue resident CD8 T cell immunity, in concert with a modulated HIV-specific CD4 T cell response that maintains low numbers of HIV targets in mucosal tissue, while providing adequate help for a strong adaptive response. 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 adjuvants coupled with native trimeric Env immunogens to induce and mechanistically dissect strong durable humoral responses. In addition, we aim to fully characterize and harness a novel population of tissue resident CD8 T cells to effectively synergize with the humoral immune response in providing protection from SHIV challenge. Because recent data suggest that SIV/HIV specific mucosal CD4 T cells could enhance infection, we will also explore the potential for modulating the susceptibility of these cells to enhance protection. In FOCUS 2, aimed at defining mechanisms of reservoir eradication, we will utilize novel latency reversing agents and immunostimulants to define an optimal viral reactivation program, and then will combine these with the optimized vaccine approaches defined in FOCUS 1 to explore the potential of this combination to yield a sustained suppression of virus replication following withdrawal of highly active antiretroviral therapy. These experimental approaches will be supported by an effective Operations and Management Support component and five state of the art Scientific Research Support Cores in order to fully characterize the magnitude, function, specificity and repertoire of the humoral response. Single cell analytics and transcriptomics will also support characterization of innate and adaptive signals at the cellular level.

 描述（由适用提供）：非人类灵长类动物的创新艾滋病研究的Emory联盟旨在了解保护和消除SIV/SHIV感染的B和T细胞生物学。该财团汇集了一系列艾滋病毒疫苗和治愈学科的高度协作和产品研究人员的跨学科组合，以解决总体假设，即成功的预防性HIV疫苗需要强大且持续的全身性和粘膜粘膜或粘膜Immunorespess，由功能抗体和抗体居民构成的hHODIC CD8 TORIM CODY CD8 T）细胞反应在粘膜组织中保持较少的HIV靶标，同时为强大的适应性反应提供足够的帮助。此外，我们假设这种潜在和平衡的疫苗反应将在主动潜伏期逆转剂的背景下减少病毒储量，从而在停止高度活跃的抗逆转录病毒疗法后维持病毒复制的抑制。旨在理解疫苗保护机制的焦点1中的方法将利用最新的调节器，并结合天然三聚合物ENV免疫原理，以诱导和机械剖析强耐用的体液反应。此外，我们旨在充分表征和利用新的组织居民CD8 T细胞种群，以有效地与体液免疫响应协同，以保护SHIV挑战。由于最近的数据表明SIV/HIV特异性粘膜CD4 T细胞可以增强感染，因此我们还将探索调节这些细胞增强保护的敏感性的潜力。在旨在定义储层装饰机制的焦点2中，我们将利用新型的延迟反向反转剂和免疫刺激物来定义最佳的病毒重新激活程序，然后将其与焦点1中定义的优化疫苗方法相结合，以探索这种抑制术的潜在抑制术的潜在，以探索较高的活跃性的撤回术语。这些实验方法将得到有效的操作和管理支持部分和五个艺术科学研究支持核心的支持，以充分表征体液反应的大小，功能，特异性和曲目。单细胞分析和转录组学还将支持细胞水平上的先天和适应性信号的表征。