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治疗的艾滋病毒感染者经历了可检测的反弹 在中断抗逆转录病毒治疗后数周内，HIV血浆病毒血症患者中， 存档储层的大小的相关性和其中减少的关键量度。最近的数学 估计表明在ART去除后每5-8天发生病毒再活化事件。免疫 迫切需要采取预防或延长病毒再激活和艾滋病毒反弹时间的战略， 在受感染的个体中持久控制或根除艾滋病毒。ART后血浆病毒反弹 中断被认为主要源于长寿命的静息CD 4 + T细胞储库，主要是PD-1+ T细胞， 次级淋巴组织（LT）如淋巴结、脾、扁桃体、骨髓内的滤泡辅助细胞， 和肠组织内的淋巴聚集体。本P01提案将探索和模拟两种免疫学 预防、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 在经传播的创始人-SHIV感染的恒河猴中的治疗（K. Bar/G. Shaw，项目1）和（2）抑制 淋巴细胞从LT中排出，既防止感染的CD 4 + T细胞重新分布， ART后淋巴组织中再活化的感染性CD 4 + T细胞和保护性CD 8 + T细胞之间的关系 在SIV感染恒河猴（M. Betts，Project 2）.重要的是，我们将使用条形码SIV 和SHIV病毒（B. Keele），使我们能够在克隆水平上精确跟踪再激活率， 并辨别潜在的病毒再激活的组织和细胞类型。这些项目将得到下列专家的支持： 数学建模（M.达文波特，分析和建模核心）和非人灵长类动物研究（M。 帕亚尔迪尼湾Silvestri非人灵长类核心）。这些研究将为以下方面提供新的见解： 免疫学策略延迟或预防ART中断后病毒反弹。 PHS 398/2590（Rev.06/09）