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、分布和动态在人与人之间存在很大差异。有 在HIV感染者（PWH）的组织中也存在相当大的异质性。因此，“一个尺寸适合所有人” 艾滋病毒治疗策略可能会失败，因为每个水库是由不同的病毒和宿主因素在其艾滋病毒专性 微环境（主页）。为了响应理解艾滋病毒库动态RFA（AI-21-013），我们的 总体HOME项目旨在阐明控制水库动态的病毒和宿主机制 在威尔斯亲王医院接受和不接受抗逆转录病毒治疗的情况下， 我们的“病毒学，流行病学，整合”（VENI）研究项目（RP）将集中在病毒因素， PWH中HIV储库动态的连续体，包括：HIV储库大小和遗传组成，HIV 整合景观，克隆扩增病毒的组织密度，表观遗传标记和前病毒染色质 完整前病毒的可及性。(The互补VIDI RP将评估细胞、免疫、药物、人体 表观遗传学和建筑HOME，维西RP将整合和分析所有数据。实验 在计划中，HIV储库动态连续体被简化为以下储库状态，即ART开启和关闭： ·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和血浆中的病毒抑制期间，当HIV在组织储库中持续存在时，留在家中。 通过从我们之前的P01（AI 131385）中获得的知识，我们的VENI RP的可行性大大增强 以及其最后一次捐赠队列，该队列从PWH收集了（n=5）或未停止的尸检标本 ART（n=15）死亡前。HOME计划将使这一独特的群体得以延续，同时大大提高 在单基因组和细胞水平上研究人体内的艾滋病病毒库。 为了实现我们的目标并优化资源分配，我们开发了一种自适应学习策略， 包括映射和确认阶段。在标测阶段，VENI RP将标测所有样本， HIV储存库的大小、组成和转录活性，VIDIRP将绘制ART和细胞环境图 在这些样本中。在确认阶段，来自感兴趣样品的活细胞将被更深入地检测。 特征在于VENI RP，以在单基因组水平上确定病毒和前病毒表观遗传因子 与预定的储层状态相关联（即，离开，回来，留在家里。在分析这些数据时， 维西RP将利用来自映射和确认阶段的数据。 在与其他RP的协同作用下，我们预计VENI RP将阐明活动中的脆弱性，反弹 和更新人体内的艾滋病毒储存库，并为新的艾滋病毒治疗策略提供信息。