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、一体化(VENI)研究项目-摘要 病毒库的大小、分布和动态在人与人之间的变异性很大。的确有 艾滋病毒(PWH)感染者体内的组织也具有相当大的异质性。因此，“一码适用于所有人” 艾滋病毒治疗策略可能会失败，因为每个宿主都受到不同的病毒和宿主因素的控制 微环境(家)。针对了解HIV水库动力学RFA(AI-21-013)，我们的 总体HOME项目旨在阐明控制储层动力学的病毒和宿主机制 全身接受和不接受抗逆转录病毒治疗(ART)。 我们的“病毒学、表观遗传学、整合”(VENI)研究项目(RP)将专注于支配病毒因素 威尔斯亲王医院中艾滋病毒储存库动力学的连续体，包括：艾滋病毒储存库的大小和基因组成 整合格局、克隆性扩展病毒的组织密度、表观遗传标记和前病毒染色质 完整的前病毒的可及性。(互补的VIDI RP将评估细胞、免疫、药物、人类 表观遗传学和建筑住宅，VICI RP将整合和分析所有数据。)用于试验性 规划中，HIV储存库动态连续体被简化为以下储存库状态： ·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。 我们从之前的P01(AI131385)中获得的知识大大增强了我们的Veni RP的可行性 和它的最后一份礼物队列，收集有(n=5)或没有停止的PWH的死前和死后样本 临死前ART(n=15)。主场计划将使这一独特的群体得以继续，同时大大 将科学扩展到在单个基因组和细胞水平上研究人体内的艾滋病毒蓄积物。 为了实现我们的目标并优化分配的资源，我们开发了一种适应性学习策略， 包括映射和确认阶段。在映射阶段，Veni RP将映射所有样本 HIV储存库的大小、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更深入地 以Veni RP为特征在单基因组水平上确定病毒和前表观遗传因子 与预定义的水库状态(即离开、到来、待在家里)相关联。在分析这些数据的过程中， VICI RP将利用测绘和确认阶段的数据。 在与其他RPS的协同中，我们预计Veni RP将阐明活动中的漏洞，反弹 以及人体内艾滋病毒蓄积物的更新，并为新的艾滋病毒治疗战略提供信息。