Delaney AIDS Research Enterprise to Cure HIV

德莱尼艾滋病研究企业治愈艾滋病毒

• 批准号: 10469472
• 负责人: STEVEN Grant DEEKS
• 金额: $ 544.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469472
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Aftercare; Animal Model; Anti-Retroviral Agents; Antigen Targeting; Apoptotic; BCL2 gene; Biological; CD8-Positive T-Lymphocytes; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Cytomegalovirus Vaccines; Development; Disease remission; Event; Frequencies; Future; Genetic Transcription; Goals; Growth; HIV; HIV Infections; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immune system; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Intercept; Interruption; Investments; Lead; Lymphoid Tissue; Mediating; Mission; Modeling; Monkeys; Nature; Pathway interactions; Persons; Pharmaceutical Preparations; Population; Predisposition; Proliferating; Proteins; Proviruses; Recrudescences; Regimen; Research; Research Design; Research Personnel; Residual state; Resistance; Resources; SIV; Sampling; Series; Signal Transduction; Sustainable Development; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Studies; Viral; Viral Antigens; Viral Proteins; Viremia; Virus; Work; adaptive immune response; antagonist; antiretroviral therapy; base; cell killing; cohort; collaboratory; combinatorial; design; humanized mouse; in vitro Model; in vivo; meetings; member; mimetics; mouse model; nonhuman primate; preclinical development; prevent; programs; response; therapy development; treatment optimization; viral RNA; viral rebound

PROJECT SUMMARY/ABSTRACT The goals of the DARE Collaboratory are to develop a viable combination regimen that reduces the rebound- competent HIV/SIV reservoir during antiretroviral therapy (ART) and/or induces durable control of HIV/SIV in the absence of therapy. Our proposed work is based on two observations made our group. First, we found that virus- specific CD8+ T cells contribute to control of the virus at steady-state. These cells, however, have limited effect during and immediately post-ART. We believe and will seek to prove that effective remission strategies will require organization of a robust innate and adaptive immune response during the earliest stages of virus rebound, effectively intercepting and suppressing viral rebound prior to the massive systemic growth of SIV/HIV that overwhelms, damages and/or evades the immune system. Second, we and others have found that despite virus expression during ART (either naturally or in response to a latency reversal agent), the frequency of infected cells remains stable. We have found that infected cells are relatively resistant to cell death programs. We will develop therapies that render these cells to host-mediated clearance mechanisms, thus resulting in their reduction and perhaps elimination. To achieve our goals, we will (1) characterize in people transcriptionally active cells and proliferating infected cells, focusing on identifying mechanisms for persistence, (2) define in people the earliest immunologic and virologic events post-interruption of ART, focusing on post-treatment controllers, (3) develop in non-human primates (NHPs) a combination regimen that targets the reactivating virus during the immediate post-ART period and results in sustained control at set-point and (4) develop in vitro and in animal models therapies that render the reservoir more susceptible to death through the activation of intrinsic (cellular) and/or extrinsic (virus-specific) pro-apoptotic pathways. This work will leverage our deep investment in (1) the optimization of the SIV NHP model and a humanized mouse model, both developed specifically to support the types of studies we will pursue, (2) the development of a robust clinical cohort (SCOPE) designed to support intensive, biologic studies of people living with HIV (PWH), and (3) the implementation and conduct of several clinical trials designed in part to test our hypotheses in people and from which samples will be made available to our team for ex vivo studies. We anticipate meeting the following milestones and deliverables: (1) definition of the active reservoir in lymphoid tissues from SIV-infected monkeys and HIV-infected humans on effective ART, (2) determination of whether reservoir cells are resistant to intrinsic and extrinsic cell killing, (3) development of a viable and translatable remission strategy in NHPs, and (4) identification and pre-clinical development of interventions aimed at enhancing the cell death, either by making cells more susceptible to cell death and/or by optimizing the efficacy of the virus-specific T cell response.

项目概要/摘要 DARE 合作实验室的目标是开发一种可行的组合方案，以减少反弹- 抗逆转录病毒治疗 (ART) 期间有效的 HIV/SIV 储存库和/或诱导对 HIV/SIV 的持久控制 缺乏治疗。我们提出的工作是基于我们小组的两项观察。首先，我们发现病毒—— 特定的 CD8+ T 细胞有助于在稳态下控制病毒。然而，这些细胞的作用有限 ART 期间和之后立即。我们相信并将努力证明有效的缓解策略将 需要在病毒的最早阶段组织强大的先天性和适应性免疫反应 反弹，在SIV/HIV大规模系统性增长之前有效拦截和抑制病毒反弹 压倒、损害和/或逃避免疫系统。其次，我们和其他人发现，尽管 ART 期间的病毒表达（自然或响应潜伏逆转剂）、感染频率 细胞保持稳定。我们发现受感染的细胞对细胞死亡程序具有相对的抵抗力。我们将 开发使这些细胞进入宿主介导的清除机制的疗法，从而导致它们 减少甚至消除。 为了实现我们的目标，我们将 (1) 表征人类转录活性细胞和增殖的感染细胞 细胞，重点是确定持久性机制，（2）定义人类最早的免疫学和 ART 中断后的病毒学事件，重点关注治疗后控制者，(3) 在非人类中发生 灵长类动物 (NHP) 一种联合治疗方案，针对 ART 治疗后立即重新激活的病毒 并导致在设定点上的持续控制，并且（4）在体外和动物模型中开发治疗方法，使 储存库更容易通过内在（细胞）和/或外在（病毒特异性）的激活而死亡 促凋亡途径。 这项工作将利用我们在 (1) SIV NHP 模型的优化和人性化 小鼠模型，都是专门为支持我们将要开展的研究类型而开发的，(2) 的开发 强大的临床队列 (SCOPE) 旨在支持对艾滋病毒感染者 (PWH) 进行深入的生物学研究， (3) 实施和开展几项临床试验，部分目的是为了在人体中检验我们的假设 以及我们的团队将获得的样本用于离体研究。 我们预计实现以下里程碑和可交付成果：(1) 淋巴液活性储库的定义 对感染 SIV 的猴子和感染 HIV 的人的组织进行有效的 ART，（2）确定是否 储库细胞对内在和外在细胞杀伤具有抵抗力，（3）开发可行且可翻译的细胞 NHP 的缓解策略，以及 (4) 确定和临床前开发旨在 通过使细胞更容易发生细胞死亡和/或通过优化功效来增强细胞死亡 病毒特异性 T 细胞反应。