Leaving, Coming, and Staying HIV Obligate Microenvironments (HOME)

总体：离开，来，和留在艾滋病毒专性微环境（主页） 摘要 抗逆转录病毒治疗前后HIV宿主动态的病毒、宿主和环境机制 (ART)要想取得成功，就必须更深入地把握这些问题。此外，在大小、分布、 和活动的水库是巨大的，虽然一个'一刀切'的艾滋病毒治疗策略是诱人的， 简化的"批量"方法不能完全捕捉艾滋病毒库动态的复杂的基本过程。 为了更好地定义在细胞和单个细胞中控制这些动态的病毒、宿主和环境因素， 基因组水平，我们的新的离开，来和留在艾滋病毒专性微环境（家庭）计划 建立在我们以前的基础设施和成功，包括我们的'最后的礼物'队列，它招收利他主义的人 在死亡前停止或未停止抗逆转录病毒治疗的艾滋病毒感染者（PWH），收集死前临床数据和有限样本， 然后进行全身快速尸检，并在死亡后6小时内采集全身样本。的 我们计划的基本原理是，使用新的单细胞和单基因组技术将带来新的 对基于批量技术的假设的看法，并帮助确定艾滋病毒储存国的脆弱性： ·当HIV在ART期间从组织（再）激活时离开家（即，"一旦ART中断，准备移动"， 如收拾行李，准备离开），并在ART中断期间引起反弹病毒血症。 ·当艾滋病毒（重新）在ART病毒血症期间通过克隆传播在组织中繁殖时， 在接受ART治疗的同时扩增HIV感染的细胞。（克隆扩增就像在家里增加家庭成员。） ·在ART和血浆病毒抑制期间，当艾滋病毒持续存在于组织储存库中时，请呆在家里。 HOME计划分为三个研究项目（RP），以研究这些油藏动态： ·病毒、表观遗传学和整合（VENI）RP将研究病毒和前病毒表观遗传因素。 ·病毒、免疫学、药物和成像（VIDI）RP将调查宿主和环境因素。 ·病毒、免疫和细胞数据集成（VICI）RP将开发所需的新方法， 复杂多维数据的集成和分析。 这三个RP将由两个核心支持：行政和数据（AD）核心将提供领导， 通信和数据服务，以及临床，外展，病理学和伦理学（COPE）核心将指导和 在道德上监督"最后的礼物"队列 我们提出的HOME计划是一个很好的资源利用，因为它创新性地直接回应了 了解艾滋病毒储库动态RFA（AI-21 - 013），并将创建更深层次的理解 艾滋病病毒库。我们希望明确定义病毒、免疫学、细胞表达、表观遗传、组织 与特定的HIV储库状态相关的结构因素在整个人体上进行和不进行ART。 这些结果将是旨在锁定或清除艾滋病毒储存库的艾滋病毒治疗策略的基础。

OVERALL: Leaving, Coming, and Staying HIV Obligate Microenvironments (HOME) ABSTRACT Viral, host and environmental mechanisms governing HIV reservoir dynamics on and off antiretroviral therapy (ART) must be grasped more deeply if cure efforts are to be successful. Further, variability in the size, distribution and activity of the reservoir is substantial, and although a ‘one size fit all’ HIV cure strategy is seducing, a reductionist ‘bulk’ approach cannot fully capture the complex underlying processes of HIV reservoir dynamics. To better define the viral, host and environmental factors that govern these dynamics at the cellular and single- genome level, our novel Leaving, Coming and Staying HIV Obligate MicroEnvironments (HOME) program builds on our previous infrastructure, and success, including our ‘Last Gift’ cohort, which enrolls altruistic people with HIV (PWH) who did or did not stop ART before death, collects pre-mortem clinical data and limited samples, then performs a full body rapid autopsy with sample collection across the body within 6 hours of death. The rationale for our program is that the use of new single-cell and single-genome technologies will bring new perspectives on assumptions built on bulk technologies and help identify vulnerabilities in HIV reservoir states: • Leaves HOME when HIV (re)activates from tissues during ART (i.e., ‘ready to move once ART is interrupted’, like packing its bag and getting ready to leave) and causes rebound viremia during ART interruption. • Comes HOME when HIV (re)populates tissues during viremia off ART and through the spread of clonally expanded HIV-infected cells while on ART. (Clonal expansion is like adding family to the home.) • Stays HOME when HIV persists in tissue reservoirs during ART and viral suppression in plasma. The HOME program is organized into three Research Projects (RP) to investigate these reservoir dynamics: • The Viral, EpigeNetics and Integration (VENI) RP will investigate viral and proviral epigenetic factors. • The Viral, Immunology, Drugs, and Imaging (VIDI) RP will investigate host and environmental factors. • The Viral, Immune, and Cellular data Integration (VICI) RP will develop new methods needed for the integration and analysis of complex multi-dimensional data. These three RPs will be supported by two cores: the Administrative and Data (AD) Core will provide leadership, communication and data services, and the Clinical, Outreach, Pathology and Ethics (COPE) Core will direct and ethically oversee the Last Gift cohort. Our proposed HOME program is a good use of resources because it innovatively responds directly to the Understanding HIV Reservoir Dynamics RFA (AI-21-013) and will create the next level of understanding of deep HIV reservoirs. We expect to clearly define the viral, immunological, cellular expression, epigenetic, tissue architectural factors associated with specified HIV reservoir states across the human body on and off ART. Such results would be foundational for HIV cure strategies aimed at locking down or clearing HIV reservoirs.