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

离开、到来和停留 HIV 义务微环境（家）

• 批准号: 10602737
• 负责人: David Mitchell Smith
• 金额: $ 259.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602737
• 关键词: Acute; Altruism; Anatomy; Animal Model; Architecture; Automobile Driving; Autopsy; Behavior assessment; Binding; Blood; CD4 Positive T Lymphocytes; Cells; Cessation of life; Clinical; Clinical Data; Clonal Expansion; Communication; Complex; Data; Enrollment; Environment; Environmental Risk Factor; Epigenetic Process; Ethics; Family; Genetic Transcription; Genome; Gifts; HIV; HIV Infections; Home; Hour; Human; Human body; Image; Immune; Immunologics; Immunology; Infrastructure; Integration Host Factors; Interruption; Knowledge; Leadership; Metaphor; Methods; Mission; Nucleic Acids; Outcome; Participant; Pathology; Persons; Pharmaceutical Preparations; Plasma; Population; Population Dynamics; Predisposition; Process; Proteins; Proviruses; Research; Research Project Grants; Resources; Sampling; Services; Social Behavior; Source; Specific qualifier value; Specimen; Technology; Time; Tissues; Viral; Viremia; Virus Integration; Virus Latency; Virus Replication; analytical method; antiretroviral therapy; biobank; cohort; data integration; data management; decay acceleration; design; flexibility; grasp; innovation; insight; latent HIV reservoir; multidimensional data; new technology; novel; novel therapeutics; outreach; pandemic disease; prevent; programs; sample collection; success; virology

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.

总体：离开，来和保持艾滋病毒专有性微环境（家） 抽象的 病毒，宿主和环境机制管理抗逆转录病毒疗法的HIV储层动力学 （艺术）如果要成功的努力，就必须更深入地掌握。此外，大小的变异性，分布 水库的活动是实质的，尽管“一尺寸适合所有艾滋病毒治愈策略”正在引人入胜，但 还原主义者的“批量”方法无法完全捕获HIV储层动力学的复杂基础过程。 为了更好地定义病毒，宿主和环境因素，这些因素在细胞和唯一方面控制这些动力学 基因组水平，我们的小说离开，来和保持艾滋病毒专有性微环境（家庭）计划 建立在我们以前的基础架构和成功的基础上，包括我们的“最后礼物”队列，招募了无私的人 与艾滋病毒（PWH）一起去世前或没有停止艺术的艾滋病毒（PWH），收集验尸临床数据并有限的样本， 然后在死亡后6小时内进行全身快速尸检，并在体内进行样品收集。这 我们计划的理由是使用新的单细胞和单基因组技术将带来新的 对基于批量技术建立的假设的观点，并有助于确定艾滋病毒水库国家的漏洞： •当艾滋病毒（Re）从艺术中激活艾滋病毒时离开家（即，“一旦中断艺术就可以移动”， 就像打包袋子并准备离开一样），并在艺术中断期间引起反弹病毒血症。 •当艾滋病毒（RE）在病毒血症脱离艺术期间填充组织并通过clonely的传播时，回家了 在ART上扩大了HIV感染的细胞。 （克隆扩张就像在家中增加家庭一样。） •当艾滋病毒在血浆中的艺术和病毒抑制期间，艾滋病毒持续存在于组织储层中时，请留在家里。 家庭计划分为三个研究项目（RP），以调查这些储层动态： •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将研究宿主和环境因素。 •病毒，免疫和细胞数据整合（VICI）RP将开发出所需的新方法 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）核心将提供领导才能， 通信和数据服务以及临床，外展，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。 我们提出的家庭计划是对资源的充分利用 了解艾滋病毒水库Dynamics RFA（AI-21-013），并将建立对深层的理解水平 艾滋病毒水库。我们期望明确定义病毒，免疫学，细胞表达，表观遗传学，组织 与人体跨艺术的特定艾滋病毒水库国家相关的建筑因素。这样的 结果将是旨在锁定或清除艾滋病毒水库的艾滋病毒治疗策略的基础。