HOPE - HIV Obstruction by Programmed Epigenetics

HOPE - 通过编程表观遗传学阻断 HIV

基本信息

批准号：
10469610
负责人：
Lishomwa C Ndhlovu
金额：
$ 533.6万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
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/10469610
关键词：
Acquired Immunodeficiency Syndrome Address Adopted Africa Architecture Biology Blood Brazil Cells Cerebrospinal Fluid Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communities Community Health Education DNA Detection Endogenous Retroviruses Ensure Epigenetic Process Excision Face Failure Foundations Funding Gene Silencing Genome engineering Gifts Goals Gut associated lymphoid tissue HIV HIV-1 Health Health Services Human Human Genome Immunosuppression Industry Infection Intake Integration Host Factors Learning Leukapheresis Life Longevity Military Personnel Mission Molecular Morbidity - disease rate Mutation Myeloid Cells National Institute of Allergy and Infectious Disease National Institute of Neurological Disorders and Stroke Obstruction Peptide Nucleic Acids Persons Pharmaceutical Preparations Proviruses Public Health Research Research Personnel Research Support Risk Sampling San Francisco Science Source Stem cell transplant Suggestion T-Lymphocyte Technology Testing Tissues Toxic effect Translations United States National Institutes of Health Viral Viral Load result Viral reservoir Virion Virus Virus Latency Virus Replication Work antiretroviral therapy antiviral immunity base base editor cell type cohort collaboratory combinatorial comorbidity cortistatin expectation improved industry partner inhibitor innovation integration site latent HIV reservoir lymph nodes member mortality next generation novel novel strategies organizational structure prevent programs recombinase restoration social stigma success tool viral rebound

项目摘要

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.

项目概要/摘要 40 年后，艾滋病毒感染者 (PLWH) 的治愈方法仍然难以捉摸，并且是 NIAID/NIH 最高的治疗方法之一尽管进行了抗逆转录病毒治疗并重新点燃了感染，但具有反弹能力的潜伏储存细胞仍然存在。由于缺乏有效的原病毒沉默，艾滋病毒阻塞的基本假设是程序化的。表观遗传学 (HOPE) 合作应用是一种新颖的“区块-锁定-切除”方法，需要长期病毒表达的持久沉默以永久切除潜伏的原病毒——将导致在没有治疗的情况下永久控制病毒是感染者中残留艾滋病毒的分级转化。提议从潜伏到沉默到永久有缺陷的原病毒，从而模仿和加速自然数百万年来，人类内源性逆转录病毒在人类基因组中所采取的路径。 HOPE 研究人员在 30 多年的专门研究的基础上提出了假设 HIV潜伏期的潜在机制、迄今为止潜伏期逆转策略尚未取得成功、最近的结果 Tat 抑制剂二脱氢皮质抑素 A (dCA) 和 ELITE 控制器表明，成功的“功能性”HIV 如果储存病毒深度沉默，并且先进的基因组技术可用，治愈可能会出现。用于直接交付的工程技术（Brec1 重组酶、肽核酸、基于 CRISPR 的编辑器）最后的致命一击：切除残余病毒以实现永久治愈中心假设将在以下时间得到检验。三个研究重点 (RF) 和三个 RF 共有的五个中心目标具体目标 (RF) 1：从机制上定义 HIV 在所有 T 细胞和骨髓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：开发并表征下一步- 控制 HIV 反弹的新一代 HIV 沉默方法具体目标 (RF) 3：禁用沉默者。通过靶向基因组工程研究 HIV-1 原病毒目标 1：确定 HIV-1 原病毒的表观遗传结构。在不同的整合位点整合原病毒，防止潜在 HIV 的永久沉默目标 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 4：向 HEV 学习目标 5：响应社区期望。 “功能性”和“经典”治疗方法与旧金山艾滋病基金会合作。基金会建立一个强大的以艺术为基础的社区教育计划，并与三位主要行业领导者合作，安进 (Amgen)、桑加莫 (Sangamo) 和星座 (Constellation) 将提供智力和物质支持，我们也参与其中。在美国、巴西和非洲对四个感染者临床队列进行临床样本分析。创新科学、知名成员、协作组织结构和里程碑驱动的研究 HOPE合作实验室的计划代表着对现状和承诺的新的实质性背离艾滋病毒治疗策略的基本新方法。