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

总体而言：离开、来到和留在艾滋病毒专属的微环境(家) 摘要 病毒、宿主和环境机制控制抗逆转录病毒治疗前后HIV储存库的动态 如果治疗努力要取得成功，就必须更深入地掌握(ART)。此外，大小、分布的可变性 虽然“一刀切”的艾滋病毒治疗策略很诱人，但 简化论者的“整体”方法不能完全捕捉艾滋病毒宿主动力学的复杂的潜在过程。 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，我们新的离开、到来和停留艾滋病毒专属微环境(家庭)计划 建立在我们以前的基础设施和成功的基础上，包括我们招收利他主义者的“最后一份礼物” 艾滋病毒(PWH)在死前是否停止抗逆转录病毒治疗，收集死前临床数据和有限的样本， 然后在死亡后6小时内进行全身快速尸检，并采集全身样本。这个 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 对建立在批量技术基础上的假设的看法，并帮助识别艾滋病毒储存状态中的脆弱性： ·在抗逆转录病毒治疗期间艾滋病毒(重新)从组织中激活时离家出走(即“一旦抗逆转录病毒治疗中断就准备行动”， 比如收拾行李准备离开)，并在艺术中断期间导致反弹的病毒血症。 ·当艾滋病毒(重新)在ART病毒血症期间和通过克隆性传播传播组织时回家 在接受抗逆转录病毒治疗时扩大艾滋病毒感染细胞。(克隆扩张就像在家里增加了家庭。) ·在抗逆转录病毒治疗和血浆病毒抑制期间，当艾滋病毒持续存在于组织储存库时，你可以呆在家里。 家庭计划分为三个研究项目(RP)，以调查这些油藏动力学： ·病毒、表观遗传和整合(VENI)RP将调查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将开发用于 集成和分析复杂的多维数据。 这三个RPS将由两个核心支持：管理和数据(AD)核心将提供领导， 通信和数据服务以及临床、外联、病理和道德(COPE)核心将指导和 从道德上监督最后的礼物队列。 我们建议的家庭计划很好地利用了资源，因为它创新性地直接响应了 了解HIV储层动力学RFA(AI-21-013)，并将创造更深层次的理解 艾滋病病毒的蓄水池。我们希望清楚地定义病毒、免疫学、细胞表达、表观遗传、组织 建筑因素与人体特定的艾滋病毒储存状态有关，无论是技术上还是技术外。是这样的 结果将是旨在锁定或清除艾滋病毒宿主的艾滋病毒治愈战略的基础。

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.