Immunological Strategies to Modulate SIV Rebound Following ART Interruption

ART 中断后调节 SIV 反弹的免疫策略

• 批准号: 10224003
• 负责人: Katharine June Bar
• 金额: $ 149.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224003
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Anti-Retroviral Agents; Antibody Therapy; Archives; Bar Codes; Binding Sites; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Equilibrium; Event; Excision; Growth; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Humoral Immunities; Immune response; Immunity; Immunologics; Immunology; Immunotherapy; Individual; Infection; Interruption; Kinetics; Location; Lymphocyte; Lymphoid; Lymphoid Tissue; Macaca mulatta; Mathematics; Measures; Modeling; Plasma; Process; RNA Interference; Reagent; Recrudescences; Reporting; Rest; SIV; Source; Spleen; Stochastic Processes; T cell response; Therapeutic; Time; Tissues; Tonsil; Viral; Viral Load result; Viremia; Virus; antiretroviral therapy; base; cell type; design; experience; human pathogen; immunological intervention; improved; in vivo; innovation; insight; latent HIV reservoir; lymph nodes; mathematical model; neutralizing antibody; nonhuman primate; novel; passive antibodies; prevent; programmed cell death protein 1; programs; simian human immunodeficiency virus; therapeutic evaluation; viral fitness; viral rebound; virology

Abstract. The majority of antiretroviral (ART) treated HIV-infected individuals experience detectable rebound in HIV plasma viremia within weeks following interruption of ART. The kinetics of rebound virus reactivation are a correlate of the size of the archived reservoir and a key measure of reductions therein. Recent mathematical estimates suggest that virus reactivation events occur every 5-8 days following ART removal. Immunologic strategies to prevent or extend the time to virus reactivation and HIV rebound are critically needed to enable durable control or eradication of HIV within infected individuals. Rebounding plasma virus following ART interruption is thought to primarily originate from long-lived resting CD4+ T cell reservoirs, largely PD-1+ T follicular helper cells, within secondary lymphoid tissue (LT) such as lymph nodes, spleen, tonsil, bone marrow, and lymphoid aggregates within gut tissue. This P01 proposal will explore and model two immunologic strategies to prevent, limit, or delay viral rebound by (1) directly targeting rebounding virus through passive nAb therapy in transmitted founder-SHIV infected rhesus macaques (K. Bar/G. Shaw, Project 1) and (2) inhibiting lymphocyte egress from LT to both prevent infected CD4+ T cell redistribution and enable the interaction between reactivated infected CD4+ T cells and protective CD8+ T cells in lymphoid tissue after ART interruption in SIV infected rhesus macaques (M. Betts, Project 2). Importantly, we will employ bar-coded SIV and SHIV viruses in both projects (B. Keele), allowing us to precisely track reactivation rate at a clonal level, and to discern potential tissue and cell types of viral reactivation. These projects will be supported by experts in mathematical modeling (M. Davenport, Analysis and Modeling Core) and nonhuman primate studies (M. Paiardini/G. Silvestri Non-Human Primate Core). Together these studies will provide novel insights into immunological strategies to delay or prevent viral rebound after ART interruption. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

抽象的。大多数接受抗逆转录病毒(ART)治疗的艾滋病毒感染者经历了可检测到的反弹。 在抗逆转录病毒疗法中断后的几周内出现艾滋病毒血浆病毒血症。反跳病毒重新激活的动力学为 存档的水库大小的相关性和其中减少的关键措施。最新数学 据估计，病毒重新激活事件在ART移除后每5-8天发生一次。免疫学 预防或延长病毒重新激活和艾滋病毒反弹的时间的战略至关重要，以实现 持久控制或根除感染者体内的艾滋病毒。抗逆转录病毒治疗后血浆病毒反弹 中断被认为主要源于长期静息的CD4+T细胞库，主要是PD-1+T细胞 滤泡辅助细胞，位于次级淋巴组织(LT)内，如淋巴结、脾、扁桃体、骨髓、 和肠道组织内的淋巴集合体。这项P01提案将探索和模拟两种免疫学 通过以下方式防止、限制或延迟病毒反弹的策略：(1)通过被动NAB直接靶向反弹病毒 方正-希氏病毒感染恒河猴的治疗(K.Bar/G.Shaw，项目1)和(2)抑制 淋巴细胞从LT流出，既防止感染的CD4+T细胞重新分布，又使相互作用成为可能 ART术后淋巴组织中再激活感染的CD4+T细胞与保护性CD8+T细胞的比较 阻断感染SIV的恒河猴(M.Betts，项目2)。重要的是，我们将使用条形码SIV 和两个项目中的SHIV病毒(B.Keele)，使我们能够在克隆水平上精确跟踪重新激活率， 并识别病毒重新激活的潜在组织和细胞类型。这些项目将得到以下领域专家的支持 数学建模(M.Davenport，分析和建模核心)和非人灵长类研究(M. Paiardini/G.Silvestri非人类灵长类核心)。总而言之，这些研究将为 延缓或防止ART阻断后病毒反弹的免疫策略。 PHS 398/2590(06/09版)页面续格式页面