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：
10313946
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/10313946
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 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 cell type cohort collaboratory combinatorial comorbidity cortistatin expectation improved industry partner inhibitor/antagonist 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.

项目摘要/弃权 40年后，治愈艾滋病毒（PLWH）的人仍然难以捉摸，也是NIAID/NIH的最高者之一优先事项。反弹能力的潜在储层细胞持续目的地抗逆转录病毒疗法并重新点燃感染由于缺乏有效的病毒沉默。通过编程的HIV阻塞的基本假设表观遗传学（HOPE）协作应用是一种新颖的“阻止锁定”方法 - 长期进入病毒表达的持久沉默朝着潜在病毒的永久惊喜 - 将导致在没有治疗的情况下，永久控制病毒。 PLWH中残留HIV的分级转化为从潜在到沉默到永久有缺陷的原病毒，从而模仿和加速自然人类内源性逆转录病毒已在人类基因组中已有数百万年的路径。这希望调查人员根据30多年的专门研究提出了假设艾滋病毒潜伏期的基本机制，迄今为止缺乏延迟策略的成功，最新结果使用TAT抑制剂Didehydro-Cortistin A（DCA）和精英控制器，表明成功的“功能性” HIV 如果储层病毒深深沉默，并且晚期基因组的可用性可能会产生治愈用于直接交付最终的政变恩典：残余病毒的永久治疗。中心假设将在三个RF之间共享的三项研究重点（RF）和五个中心目标。特定目标（RF）1：通过机械定义HIV在所有T-和髓样细胞子集中的持久转录沉默关键宿主和病毒因素的组合靶向。特定目标（RF）2：开发和表征下一步艾滋病毒沉默的生成方法在控制艾滋病毒反弹方面。特定目标（RF）3：禁用沉默针对性基因组工程的HIV-1病毒。目标1：确定表观遗传结构在不同整合地点进行的综合病毒阻止了潜在艾滋病毒的永久沉默。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3：识别 TAT的分子功能和宿主因子，以防止永久沉默。目标4：向HERV学习人类基因组中的沉默和突变衰减。目标5：回应周围的社区期望 “功能性”和“古典”治疗方法。希望合作与旧金山艾滋病合作建立强大的基于艺术的社区教育计划，并与三名主要行业领导者一起建立基金会， Amgen，Sangamo和Constellation，他们将提供近视和唯物主义的支持。我们也参与了在美国，巴西和非洲，有四个用于临床样本分析的临床PLWH。集体，创新的科学，著名成员，协作组织结构和里程碑式的研究希望的计划合作组织代表了与现状的新事物，并承诺艾滋病毒治愈策略的基本新方法。