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: 10626936
• 负责人: STEVEN Grant DEEKS
• 金额: $ 545.24万
• 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/10626936
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Address; Aftercare; Animal Model; Anti-Retroviral Agents; Antigens; Apoptotic; BCL1 Oncogene; Binding; 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 Evasion; Immune response; Immune system; Immunologics; Immunotherapy; In Vitro; Individual; Infection; Innate Immune Response; Intercept; Interruption; Investments; 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; T cell response; T-Lymphocyte; Testing; Therapeutic; Viral; Viral Antigens; Viral Proteins; Viremia; Virus; Work; acute infection; adaptive immune response; antagonist; antiretroviral therapy; 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.

项目总结/摘要 DARE合作实验室的目标是开发一种可行的组合方案，减少反弹- 在抗逆转录病毒治疗（ART）过程中有效的HIV/SIV储库和/或诱导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个观察结果。首先我们发现了病毒 特异性CD 8 + T细胞有助于控制病毒的稳定状态。然而，这些细胞的作用有限， 我们相信并将努力证明，有效的缓解策略将 需要在病毒感染的最早阶段组织强有力的先天性和适应性免疫应答， 反弹，在SIV/HIV的大规模系统性生长之前有效地拦截和抑制病毒反弹 它会破坏、破坏和/或逃避免疫系统。第二，我们和其他人发现，尽管 ART期间的病毒表达（天然的或响应于潜伏逆转剂），感染的频率， 细胞保持稳定。我们已经发现，受感染的细胞对细胞死亡程序具有相对抵抗力。我们将 开发使这些细胞进入宿主介导的清除机制的疗法，从而导致其 减少，甚至消除。 为了实现我们的目标，我们将（1）在人的转录活性细胞和增殖感染的特点 细胞，专注于识别持久性的机制，（2）在人类中定义最早的免疫学， ART中断后的病毒学事件，重点是治疗后控制者，（3）在非人类中发生 灵长类动物（NHP）的联合方案，目标是在立即后ART期间的再活化病毒 并导致在设定点的持续控制，以及（4）开发体外和动物模型疗法， 通过激活内源性（细胞）和/或外源性（病毒特异性） 促凋亡途径。 这项工作将利用我们在以下方面的深度投资：（1）SIV NHP模型的优化和人性化的 小鼠模型，两者都是专门为支持我们将进行的研究类型而开发的，（2）开发 一个强大的临床队列（SCOPE），旨在支持对艾滋病毒感染者（PWH）进行密集的生物学研究， 以及（3）实施和进行几项临床试验，部分旨在测试我们对人体的假设 并将从中提取的样本提供给我们的团队进行体外研究。 我们预计将达到以下里程碑和可交付成果：（1）淋巴细胞活性库的定义 来自SIV感染的猴子和HIV感染的人的有效ART的组织，（2）确定是否 储库细胞对内源性和外源性细胞杀伤具有抗性，（3）开发出一种可行的和可翻译的细胞， NHP的缓解策略，以及（4）确定和临床前开发干预措施， 通过使细胞对细胞死亡更敏感和/或通过优化功效来增强细胞死亡 病毒特异性T细胞反应的机制

项目成果

Viral competition assay to assess the role of HIV-1 proteins in immune evasion.

• DOI: 10.1016/j.xpro.2022.102025
• 发表时间: 2023-03-17
• 期刊: STAR PROTOCOLS
• 作者: Duette, Gabriel;Cronin, Samantha;Kelleher, Anthony D.;Palmer, Sarah
• 通讯作者: Palmer, Sarah

Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and/or CTLA-4.

• DOI: 10.3389/fimmu.2023.1064346
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Fisher K;Schlub TE;Boyer Z;Rasmussen TA;Rhodes A;Hoh R;Hecht FM;Deeks SG;Lewin SR;Palmer S
• 通讯作者: Palmer S

Evolving Strategies to Eliminate the CD4 T Cells HIV Viral Reservoir via CAR T Cell Immunotherapy.

• DOI: 10.3389/fimmu.2022.873701
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Markers of Immune Activation and Inflammation Are Associated with Higher Levels of Genetically-Intact HIV in HIV-HBV Co-Infected Individuals.

• DOI: 10.1128/jvi.00588-22
• 发表时间: 2022-08-24
• 期刊: JOURNAL OF VIROLOGY
• 影响因子: 5.4
• 作者: Wang, Xiao Qian;Zerbato, Jennifer M.;Avihingsanon, Anchalee;Fisher, Katie;Schlub, Timothy;Rhodes, Ajantha;Audsley, Jennifer;Singh, Kasha P.;Zhao, Wei;Lewin, Sharon R.;Palmer, Sarah
• 通讯作者: Palmer, Sarah

Near full-length HIV sequencing in multiple tissues collected postmortem reveals shared clonal expansions across distinct reservoirs during ART.

对死后收集的多个组织进行近全长 HIV 测序揭示了 ART 期间不同储存库之间的共享克隆扩增。

• DOI: 10.1016/j.celrep.2023.113053
• 发表时间: 2023
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Dufour,Caroline;Ruiz,MariaJulia;Pagliuzza,Amélie;Richard,Corentin;Shahid,Aniqa;Fromentin,Rémi;Ponte,Rosalie;Cattin,Amélie;WicheSalinas,TomasRaul;Salahuddin,Syim;Sandstrom,Teslin;Schinkel,StephanieBurke;Costiniuk,CeciliaT;Jen
• 通讯作者: Jen