Immunological Strategies to Modulate SIV Rebound Following ART Interruption

ART 中断后调节 SIV 反弹的免疫策略

基本信息

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
项目类别：
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

项目摘要

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。大多数抗逆转录病毒（ART）治疗的艾滋病毒感染者经历了可检测的反弹在ART中断后数周内，在HIV血浆病毒血症中。反弹病毒重新激活的动力学是存档储层的大小和其中的关键量度的相关性。最近的数学估计表明病毒重新激活事件发生在ART去除后每5-8天发生一次。免疫学需要迫切需要预防或延长病毒重新激活和艾滋病毒反弹时间的策略以实现受感染个体内的持久控制或根除HIV。反弹后的血浆病毒在艺术之后中断被认为主要起源于长寿命的静止CD4+ T细胞储存库，在很大程度上PD-1+ T 卵泡辅助细胞，次要淋巴组织（LT），例如淋巴结，脾脏，扁桃体，骨髓，和肠道组织中的淋巴骨料。该P01提案将探索和模拟两个免疫学通过（1）通过被动NAB直接靶向反弹病毒的预防，限制或延迟病毒反弹的策略在传播的创建者SHIV感染的恒河猕猴（K. Bar/g。Shaw，项目1）和（2）抑制的治疗中淋巴细胞从LT出口到预防感染的CD4+ T细胞重新分布并启用相互作用在ART后，在淋巴组织中重新激活感染的CD4+ T细胞和保护性CD8+ T细胞之间 SIV感染恒河猕猴的中断（M. Betts，项目2）。重要的是，我们将采用钢筋编码的SIV 和两个项目中的SHIV病毒（B. Keele），使我们能够精确跟踪克隆水平的重新激活率，并辨别病毒重新激活的潜在组织和细胞类型。这些项目将得到专家的支持数学建模（M. Davenport，分析和建模核心）和非人类灵长类动物研究（M. paiardini/g。 Silvestri非人类灵长类动物核心）。这些研究将共同提供新颖的见解免疫学策略延迟或预防艺术中断后病毒反弹。 PHS 398/2590（修订版06/09）页面延续格式页面