Project 002 - VIDI

项目 002 - VIDI

• 批准号: 10602744
• 负责人: Sara Gianella Weibel
• 金额: $ 67.56万
• 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/10602744
• 关键词: Antigens; Architecture; Area; Autopsy; Binding; Biological Assay; Blood; CCR6 gene; CD4 Positive T Lymphocytes; Cells; Cessation of life; Chromatin; Clonal Expansion; Data Analyses; Data Set; Detection; Effector Cell; Environment; Environmental Risk Factor; Epigenetic Process; Family; Fire - disasters; Genes; Genetic Transcription; Genome; Gifts; Goals; HIV; HIV Infections; Home; Human body; Image; Imaging technology; Immune; Immunology; Inflammation; Integration Host Factors; Interruption; Intrinsic factor; Investigation; Knowledge; Lymphoid Tissue; Maps; Microscopy; Mucous Membrane; Natural Killer Cells; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Plasma; Population Dynamics; Population Process; Predisposition; Process; Provirus Integration; Proviruses; Research Project Grants; Resource Allocation; Running; Sampling; Science; Shock; Site; Source; Specimen; Surface; Techniques; Technology; Tissues; Viral; Viral Physiology; Viremia; Virus; adaptive learning; antiretroviral therapy; brain tract; cohort; comorbidity; end of life; high dimensionality; improved; in vivo; inflammatory milieu; innovation; insight; interest; pharmacologic; programmed cell death protein 1; programs; reproductive tract; single cell technology; social stigma; success; therapeutic target; viral rebound

PROJECT 2. Viral Immunology, Drugs, and Imaging (VIDI) Research Project - ABSTRACT Despite the success of antiretroviral therapy (ART) improving the lives of persons with HIV (PWH), curing HIV would be important to reduce stigma and long-term co-morbidities associated with HIV infection that occur even during ART. Developing a successful cure will need to better identify the viral and host factors that govern HIV dynamics in its HIV Obligate MicroEnvironment (HOME) to identify reservoir vulnerabilities that can be targeted. The Viral Immunology, Drugs, and Imaging (VIDI) Research Project (RP) will focus on immune, pharmacological, host epigenetic cellular environments, and tissue architecture that govern the continuum of HIV reservoir dynamics. This characterization by the VIDI RP alone will add considerable new knowledge to the field. In the HOME program, these assay results will be integrated with viral features of HIV reservoir dynamics characterized by VENI RP, and all datasets will be further integrated and analyzed by VICI RP. For experimental planning, the HIV reservoir dynamic continuum is simplified as the following reservoir states: · Leaves HOME when HIV (re)activates from tissues during antiretroviral therapy (ART) (i.e., 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 (silently) persists in blood and tissue reservoirs (on and off ART). To optimize allocated resources, we developed a two-step Adaptive Learning Approach. During the Mapping phase, the VIDI RP will examine how cellular and soluble inflammatory milieus and ART levels are associated with each reservoir state (i.e., leaving, coming, staying). The VICI RP will assist in the integration and analysis of these data to identify ‘samples-of-interest’ that have pre-defined reservoir states and sufficient cellular environment for deeper investigation. In the Confirmation phase, the VIDI RP will use single-cell and imaging technologies to further characterize environmental factors associated with reservoir dynamics at a deeper level. Importantly, the feasibility of our VIDI 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 cohort while expanding the science to study HIV dynamics across the human body at the single-genome and single-cell level. In summary, the overall HOME program will provide a deep delineation of environmental factors governing HIV reservoir dynamics, which is directly responsive to the Understanding HIV Reservoir Dynamics RFA AI-21-013. This new knowledge will inform HIV cure strategies aiming at reversing latency (“Shock and Kill”) or at silencing permanently deep reservoirs (“Block and Lock”) and provide new insights in ways to reduce local HIV-associated tissue damage, which has been implicated in inflammation-related illnesses.

项目2。病毒免疫学，药物和成像（VIDI）研究项目 - 摘要 尽管抗逆转录病毒疗法（ART）改善了艾滋病毒（PWH）的生活，但治愈艾滋病毒的生活 减少与艾滋病毒感染相关的污名和长期合并症至关重要 在艺术期间。开发成功的治愈方法将需要更好地识别控制艾滋病毒的病毒和宿主因素 其HIV专有性微环境（家庭）中的动态，以识别可以针对目标的储层漏洞。 病毒免疫学，药物和成像（VIDI）研究项目（RP）将重点放在免疫，药物，药物， 宿主的表观遗传细胞环境以及控制HIV储层连续体的组织结构 动力学。仅Vidi RP的这种表征将为该领域增加大量的新知识。在 家庭计划，这些评估结果将与HIV储层动力学的病毒特征集成在一起 Veni RP和所有数据集将通过VICI RP进一步整合和分析。 对于实验计划，HIV储层动态连续体被简化为以下储层所述： ·当抗逆转录病毒疗法（ART）中艾滋病毒（RE）从组织中激活艾滋病毒时离开家（即 行李和准备离开），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（默默地）持续在血液和组织储层中（开关艺术）时，留在家里。 为了优化分配的资源，我们开发了两步自适应学习方法。在映射期间 阶段，Vidi RP将检查细胞和固体炎症环境和艺术水平如何相关 每个水库状态（即离开，来，留下）。 VICI RP将有助于整合和分析 在这些数据中，可以识别具有预定固定储量状态和足够蜂窝的“利益样本” 深入投资的环境。在确认阶段，Vidi RP将使用单细胞和成像 进一步表征与储层动力学相关的环境因素的技术。 重要的是，我们以前的P01所获得的知识极大地增强了我们的Vidi RP的可行性 （AI131385）及其最后的礼物队列，从PWH收集PWH前后的标本（n = 5） 或在死亡前没有停止艺术（n = 15）。家庭计划将允许该队列继续 扩展科学以在单基因组和单细胞水平上研究人体跨身体的HIV动力学。 总而言之，整个家庭计划将对有关艾滋病毒的环境因素进行深入讨论 储层动力学，直接响应理解HIV储层动力学RFA AI-21-013。 这些新知识将为艾滋病毒治愈策略提供旨在扭转潜伏期（“震惊和杀死”）或沉默 永久性深层水库（“块和锁”），并以减少当地艾滋病毒相关的方式提供新见解 组织损伤已在炎症相关疾病中暗示。