Project 001 - VINI

项目001-VINI

• 批准号: 10459874
• 负责人: David Mitchell Smith
• 金额: $ 33.18万
• 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/10459874
• 关键词: Architecture; Biological Assay; Cardiovascular Diseases; Cell Survival; Cells; Cessation of life; Chromatin; Clonal Expansion; Cytosine; Data; Data Analyses; Epigenetic Process; Family; Genes; Genetic; Genetic Transcription; Genome; Gifts; Goals; HIV; Heterogeneity; Home; Human; Human body; Immune; Immunotherapeutic agent; Inflammation; Integration Host Factors; Interruption; Knowledge; Malignant Neoplasms; Maps; Methylation; Neurocognitive Deficit; Persons; Phase; Plasma; Population Dynamics; Population Process; Process; Proviruses; Research; Research Project Grants; Resources; Running; Sampling; Science; Shock; Specimen; Technology; Tissues; Tropism; Viral; Viral reservoir; Viremia; Virus; Virus Replication; adaptive learning; antiretroviral therapy; cohort; density; design; experimental study; human tissue; insight; interest; latent HIV reservoir; learning strategy; novel therapeutics; prevent; programs; response; synergism; therapy development; viral rebound; virology

PROJECT 1. Virology, Epigenetics, Integration (VENI) Research Project - ABSTRACT Person-to-person variability in the size, distribution and dynamics of the viral reservoir is substantial. There is also considerable heterogeneity within a person with HIV (PWH) across their tissues. Thus, a ‘one size fit all’ HIV cure strategy will likely fail, as each reservoir is governed by different viral and host factors in its HIV Obligate MicroEnvironment (HOME). In response to the Understanding HIV Reservoir Dynamics RFA (AI-21-013), our overall HOME project is designed to elucidate the viral and host mechanisms governing reservoir dynamics throughout the body of PWH on and off antiretroviral therapy (ART). Our “Virology, EpigeNetics, Integration” (VENI) Research Project (RP) will focus on the viral factors that govern the continuum of HIV reservoir dynamics in PWH including: HIV reservoir size and genetic composition, HIV integration landscape, tissue density of clonally expanded virus, epigenetic marks and proviral chromatin accessibility of intact provirus. (The complementary VIDI RP will evaluate the cellular, immune, drug, human epigenetics and architectural HOMEs, and the VICI RP will integrate and analyze all data.) For experimental planning, the HIV reservoir dynamic continuum is simplified as the following reservoir states on and off ART: · 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 feasibility of our VENI RP is greatly enhanced by the knowledge gained from our previous P01 (AI131385) and its Last Gift Cohort, which collects pre- and post-mortem specimens from PWH who did (n=5) or did not stop ART (n=15) before death. The HOME program will allow the continuation of this unique cohort while greatly expanding the science to study HIV reservoirs across the human body at the single genome and cellular level. To achieve our objectives and optimize allocated resources, we developed an Adaptive Learning strategy that consists of Mapping and Confirmation phases. During the Mapping phase, the VENI RP will map all samples for HIV reservoir size, composition, and transcriptional activity, and the VIDI RP will map the ART and cellular milieus in these samples. In the Confirmation phase, viable cells from the samples-of-interest will be more deeply characterized by the VENI RP to determine viral and provial epigenetic factors at the single genome level associated with pre-defined reservoir states (i.e., leaving, coming, staying HOME). During analysis of these data, the VICI RP will make use of data from both the Mapping and Confirmation phases. In synergy with the other RPs, we expect that the VENI RP will elucidate the vulnerabilities in the activity, rebound and renewal of the HIV reservoir across the human body and inform new HIV cure strategies.

项目 1. 病毒学、表观遗传学、整合 (VENI) 研究项目 - 摘要 病毒库的大小、分布和动态的人与人之间存在很大差异。有 HIV 感染者 (PWH) 的各个组织也存在相当大的异质性。因此，“一刀切” HIV治愈策略可能会失败，因为每个病毒库都受到其HIV义务中不同病毒和宿主因素的控制 微环境（主页）。为了响应理解 HIV 储存动态 RFA (AI-21-013)，我们的 整个 HOME 项目旨在阐明控制储存库动力学的病毒和宿主机制 整个感染者全身都在接受和停止抗逆转录病毒治疗 (ART)。 我们的“病毒学、表观遗传学、整合”（VENI）研究项目（RP）将重点关注控制病毒的因素 艾滋病毒感染者中艾滋病毒储存库动态的连续性，包括：艾滋病毒储存库大小和遗传组成、艾滋病毒 整合景观、克隆扩增病毒的组织密度、表观遗传标记和原病毒染色质 完整原病毒的可及性。 （互补的 VIDI RP 将评估细胞、免疫、药物、人类 表观遗传学和建筑 HOME，VICI RP 将整合和分析所有数据。）用于实验 在规划中，HIV 病毒库动态连续体被简化为 ART 期间和非 ART 期间的以下病毒库状态： · 在 ART 期间，当 HIV 从组织中（重新）激活时离开家（即“一旦 ART 中断就准备好移动”） 例如收拾行李并准备离开），并在 ART 中断期间导致病毒血症反弹。 · 当 HIV 在 ART 后的病毒血症期间以及通过克隆性传播在组织中（重新）繁殖时，您就回家了 在 ART 期间扩增了 HIV 感染细胞。 （克隆扩张就像在家里增添家人一样。） · 在 ART 和血浆病毒抑制期间，当 HIV 在组织储存库中持续存在时，请留在家中。 我们从之前的 P01 (AI131385) 中获得的知识大大增强了 VENI RP 的可行性 及其最后的礼物队列，从停止（n = 5）或未停止的 PWH 收集死前和死后样本 死亡前接受 ART (n=15)。 HOME 计划将允许这个独特的群体继续下去，同时极大地 扩大科学范围，在单个基因组和细胞水平上研究人体中的艾滋病毒储存库。 为了实现我们的目标并优化分配的资源，我们制定了自适应学习策略 由映射和确认阶段组成。在映射阶段，VENI RP 将映射所有样本 HIV 储存库大小、组成和转录活性，VIDI RP 将绘制 ART 和细胞环境图 在这些样本中。在确认阶段，来自感兴趣样本的活细胞将被更深入地 以 VENI RP 为特征，在单基因组水平上确定病毒和原始表观遗传因素 与预定义的水库状态相关（即离开、到来、呆在家里）。在分析这些数据的过程中， VICI RP 将利用映射和确认阶段的数据。 与其他 RP 协同作用，我们预计 VENI RP 将阐明活动中的漏洞、反弹 以及人体艾滋病毒储存库的更新，并为新的艾滋病毒治疗策略提供信息。