Delaney AIDS Research Enterprise to Cure HIV

项目摘要/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- 在抗逆转录病毒治疗(ART)期间和/或在抗逆转录病毒治疗(ART)期间诱导持久控制艾滋病毒/SIV 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，我们发现了这种病毒- 在稳定状态下，特定的CD8+T细胞有助于控制病毒。然而，这些细胞的作用有限。 在艺术期间和艺术后立即。我们相信，并将努力证明，有效的缓解战略将 在病毒的最早阶段需要组织强大的先天和适应性免疫反应 在SIV/HIV大规模系统性增长之前，有效拦截和抑制病毒反弹 这会压倒、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(自然或对潜伏期反转剂的响应)，感染的频率 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。我们会 开发治疗方法，使这些细胞进入宿主介导的清除机制，从而导致它们 减少，也许是消除。 为了实现我们的目标，我们将(1)表征人的转录活性细胞和增殖感染 细胞，专注于识别持久的机制，(2)在人类中定义最早的免疫学和 ART中断后的病毒学事件，重点是后处理控制器，(3)在非人类中发展 灵长类动物(NHP)是一种联合方案，在ART后立即针对重新激活的病毒 以及(4)在体外和动物模型治疗方面的发展。 通过激活内在的(细胞的)和/或外在的(病毒特异性的)更容易死亡的宿主 促凋亡途径。 这项工作将充分利用我们在(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携带者(PWH)进行密集的生物学研究， 以及(3)一些临床试验的实施和实施，部分目的是为了在人体上测试我们的假设 其中的样本将提供给我们的团队进行体外研究。 我们期望达到以下里程碑和交付成果：(1)淋巴组织中活性储存库的定义 来自SIV感染的猴子和HIV感染的人的组织进行有效的ART，(2)确定 储藏细胞对内源性和外源性细胞杀伤具有抵抗力，(3)发育出一种可存活和可翻译的 NHP的缓解战略，以及(4)针对以下目标的干预措施的确定和临床前发展 通过使细胞更容易死亡和/或通过优化疗效来增强细胞死亡 病毒特异性T细胞反应。

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.