HOPE - HIV Obstruction by Programmed Epigenetics

项目总结/ABSTACT 40年后，对艾滋病毒携带者(PLWH)的治愈仍然难以捉摸，也是NIAID/NIH最高的之一 优先事项。尽管接受了抗逆转录病毒治疗并重新引发感染，但具有反弹能力的潜伏储存库细胞仍然存在 由于缺乏有效的前病毒沉默。人类免疫缺陷病毒程序化阻塞的基本假说 表观遗传学(HOPE)合作实验室应用是一种新的“块-锁-切除”方法--需要长期 持久沉默病毒表达以永久切除潜伏期前病毒-将导致 在没有治疗的情况下永久控制病毒。PLWH中残留HIV的分级转化是 建议从潜伏到沉默到永久有缺陷的普鲁斯，从而模仿和加速自然 人类内源性逆转录病毒在数百万年来进入人类基因组的路径。这 这一假说是基于HOPE调查人员30年来对 艾滋病毒潜伏期的潜在机制，潜伏期逆转策略迄今缺乏成功，最新结果 TAT抑制剂二氢皮质酮A(DCA)和精英控制器表明，成功的“功能性”艾滋病毒 如果水库病毒的深度沉默，以及先进基因组的可用性，就可能出现治愈- 用于直接投递的工程技术(Brec1重组酶、肽核酸、基于CRISPR的编辑) 最后的妙招：根治残存的病毒。核心假设将在#年进行检验。 三个研究重点(RFS)和三个RFS共享的五个中心目标。特定目标(RF)1： 从机制上定义艾滋病毒在所有T细胞和髓系细胞亚群中的持久转录沉默 关键宿主和病毒因子的组合靶向。特定目标(RF)2：开发和描述NEXT- 世代HIV沉默方法在控制HIV反弹中的作用。特定目标(RF)3：禁用静音器 靶向基因组工程的HIV-1前病毒。目标1：确定细胞的表观遗传结构 在不同的整合部位整合前病毒，防止潜伏的艾滋病毒永久沉默。目标2： 在分子水平上定义有利于病毒反弹的细胞类型和表观遗传细胞状态。目标3：确定 TAT的分子功能和防止永久沉默的宿主因子。目标4：向Herv学习 人类基因组中的沉默和突变衰退。目标5：回应周围社区的期望 “功能性”和“经典性”治疗方法。希望合作实验室与旧金山艾滋病协会合作 基金会建立了一个强大的以艺术为基础的社区教育计划，并与三位主要的行业领导者， 安进、桑加莫和星座，他们将提供智力和物质上的支持。我们还参与了 在美国、巴西和非洲与PLWH的四个临床队列进行临床样本分析。总体而言， 创新的科学，知名的成员，协作的组织结构和里程碑驱动的研究 希望合作实验室计划代表着与现状和承诺的新的实质性背离 一种根本性的艾滋病毒治疗战略新方法。

PROJECT SUMMARY/ABSTACT After 40 years, a cure for people living with HIV (PLWH) remains both elusive and one of NIAID/NIH’s highest priorities. Rebound-competent latent reservoir cells persist despite antiretroviral therapy and rekindle infection due to the lack of efficient proviral silencing. The underlying hypothesis of the HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory application is a novel “block-lock-excise” approach—that entails the long-term durable silencing of viral expression towards permanent excision of the latent provirus—will lead to the permanent control of the virus in the absence of therapy. A graded transformation of remnant HIV in PLWH is proposed from latent into silent to permanently defective proviruses, thus emulating and accelerating the natural path that human endogenous retroviruses have taken in the human genome over millions of years. This hypothesis was formulated on the basis of 30+ years of dedicated research by HOPE investigators into the underlying mechanisms of HIV latency, lack of success to date with latency-reversing strategies, recent results with Tat inhibitor didehydro-Cortistatin A (dCA) and ELITE controllers showing that a successful ‘functional’ HIV cure could arise if there is a deep silencing of reservoir virus, and the availability of advanced genome- engineering technologies (Brec1 recombinase, peptide nucleic acids, CRISPR-base editors) for direct delivery of the final coup de grace: excision of remnant virus for permanent cure. The central hypothesis will be tested in three Research Focuses (RFs) and five central objectives shared between the three RFs. Specific Aim (RF) 1: Define mechanistically the durable transcriptional silencing of HIV across all T- and myeloid cell subsets by combinatorial targeting of key host and viral factors. Specific Aim (RF) 2: Develop and characterize next- generation HIV silencing approaches in the control of HIV rebound. Specific Aim (RF) 3: Disable the silenced HIV-1 provirus by targeted genome engineering. Objective 1: Determine the epigenetic architecture of the integrated provirus at different integration sites that prevents permanent silencing of latent HIV. Objective 2: Define, at the molecular level, cell types and epigenetic cell states that favor viral rebound. Objective 3: Identify molecular functions of Tat and host factors that prevent permanent silencing. Objective 4: Learn from HERV silencing and mutational decay in the human genome. Objective 5: Respond to community expectations around ‘functional’ and ‘classical’ cure approaches. The HOPE Collaboratory partnered with the San Francisco AIDS Foundation to build a strong art-based community education program and with three primary industry leaders, Amgen, Sangamo and Constellation, who will provide intellectual and materialistic support. We also engaged with four clinical cohorts of PLWH for clinical sample analysis in the US, Brazil and Africa. Collectively, the innovative science, renowned members, collaborative organizational structure and milestone- driven research plan of the HOPE Collaboratory represents a new and substantive departure from the status quo and promises a fundamental new approach to HIV Cure strategies.