Mentoring Scientists for Careers in HIV Translational Clinical Research

指导科学家从事艾滋病毒转化临床研究

• 批准号: 10762827
• 负责人: Timothy Jensen Henrich
• 金额: $ 19.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762827
• 关键词: Address; Aftercare; Anatomy; Autopsy; Award; Body Burden; CD4 Positive T Lymphocytes; Cell Therapy; Cell surface; Cells; Clinical; Clinical Research; Combination immunotherapy; Custom; DNA; Data; Development; Discipline of Nuclear Medicine; Disease remission; Drug Kinetics; Environment; Exhibits; Fostering; Funding; Gene Modified; Genetic; Genetic Transcription; Genomic approach; Genomics; Goals; Grant; HIV; HIV Infections; HIV envelope protein; Human; Image; Immune; Immune response; ImmunoPET; Immunofluorescence Immunologic; Immunohistochemistry; Immunology; Immunotherapeutic agent; Immunotherapy; In Situ; In Situ Hybridization; Individual; Infection; Infection Control; Inflammation; Interdisciplinary Study; Intervention; Intervention Studies; Kinetics; Knowledge; Life Cycle Stages; Location; Lymph Node Tissue; Lymphoid Tissue; Magnetic Resonance Imaging; Measures; Mentors; Mentorship; Methods; Microdialysis; Mid-Career Clinical Scientist Award (K24); Modeling; Monitor; Outcome; Participant; Pathogenesis; Persons; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Play; Population; Positron-Emission Tomography; Principal Investigator; Proliferating; Proteomics; Publications; RNA; Regional Anatomy; Research; Research Personnel; Residual state; Role; Sampling; Scientist; Site; Sudden Death; T-Cell Activation; T-Lymphocyte; TNFRSF8 gene; Techniques; Technology; Therapeutic; Therapeutic Intervention; Thinking; Time; Tissues; Tracer; Training; Transcript; Tumor Markers; Viral; Viral Physiology; Virus; biomarker discovery; career; cell motility; chimeric antigen receptor T cells; clinical translation; cohort; collaboratory; curative treatments; design; digital; experience; first-in-human; imaging modality; imaging study; improved; in vivo; innate immune pathways; innovation; insight; latent HIV reservoir; lymph nodes; minimally invasive; multidisciplinary; nano-string; new technology; novel; nuclear imaging; participant enrollment; patient oriented; patient oriented research; programs; purge; response; tool; trafficking; transcriptomics; viral genomics; viral rebound

ABSTRACT/SUMMARY The primary goals of this K24 award are to identify and cultivate diverse, highly motivated, young investigators with a propensity for independent thinking, and increase their involvement in collaborative, patient-oriented HIV pathogenesis and cure research. Specifically, junior investigators will be directed engaged in innovative methods to characterize whole-body HIV persistence and determine mechanisms of host control of HIV infection; research will foster their academic careers. One of the major barriers to the successful design and implementation of HIV curative strategies is the limited ability to characterize the tissue-wide burden of HIV in the setting of ART and monitor changes in HIV reservoirs relative to a therapeutic intervention. There is also a paucity of data of how host immune and genetic responses in these microenvironments modulate HIV persistence or exert immune control of virus without ART. Novel methods are urgently needed to address this fundamental gap in knowledge and to develop tools to evaluate curative strategies. The goals of this proposal are to: (1) determine relationships between residual HIV persistence and activity, T cell trafficking, and tissue pharmacokinetics in PWH that exhibit exceptional elite control or post-treatment control following HIV curative therapeutic intervention, (2) determine the relationship between longitudinal tissue PK of HIV bnAbs, ART and viral dynamics using immunoPET imaging and lymph node microdialysis in the setting of cure interventions, and, (3) determine the impact of HIV tissue burden and residual transcriptional activity on host cell factors in study participants enrolled in unique clinical studies and from tissue from victims of sudden death with HIV on ART. These aims involve innovative methods, such as magnetic resonance (MR) imaging studies of the HIV envelope-specific tracer, 89Zr-VRC01, and [18F]F-AraG, which is selectively taken up by activated T cell, and in- situ digital spatial profile analysis of tissue microenvironments which have customized to identify multiple HIV transcripts representing various stages of the HIV lifecycle combined with unbiased human transcriptomic analysis and targeted proteomics. Ultimately these studies will help direct interventional studies to purge HIV reservoirs and maintain viral immune control following cessation of ART. These aims are representative of the principal investigator's collaborative research program combining pathogenesis-based translational and patient-oriented research to target latent HIV reservoirs and improve immune control of residual infection. Furthermore, they expand on individually and collaboratively funded initiatives to enable long-term mentorship and support opportunities to junior investigators to become involved in translational HIV cure research.

摘要/摘要 该K24奖的主要目标是识别和培养多样的，积极进取的年轻调查员 具有独立思考的倾向，并增加了他们参与协作，以患者为导向的艾滋病毒 发病机理和治愈研究。具体而言，初级调查人员将被指导从事创新 表征全身HIV持久性并确定艾滋病毒宿主控制机制的方法 感染;研究将培养他们的学术职业。成功设计的主要障碍之一 艾滋病毒治愈策略的实施是表征艾滋病毒范围内艾滋病毒负担的能力有限 相对于治疗干预，艺术和监测HIV储层的变化的设置。还有一个 这些微环境中宿主免疫和遗传反应如何调节HIV的数据很少 没有艺术的持久性或对病毒的免疫控制。迫切需要新的方法来解决这个问题 知识的根本差距并开发用于评估治疗策略的工具。该提议的目标 为：（1）确定残留的HIV持久性与活动，T细胞运输和组织之间的关系 HIV治疗后，PWH中的药代动力学表现出卓越的精英控制或治疗后控制 治疗干预，（2）确定HIV BNABS，ART和ART和 在治疗干预措施的情况下，使用免疫集成像和淋巴结微透析的病毒动力学， （3）确定HIV组织负担和残留转录活性对宿主细胞因子的影响 研究参与者参加了独特的临床研究和来自艾滋病毒突然死亡受害者的组织 艺术。这些目的涉及创新方法，例如HIV的磁共振（MR）成像研究 包膜特异性示踪剂，89ZR-VRC01和[18F] F-arag，它们被激活的T细胞和In-选择性地占用 自定义以识别多发HIV的组织微环境的现场数字空间概况分析 代表HIV生命周期的各个阶段的成绩单与无偏的人类转录组相结合 分析和靶向蛋白质组学。最终，这些研究将有助于直接介入研究清除HIV 停止艺术后，水库并保持病毒免疫控制。这些目标是代表 首席研究者的协作研究计划，结合了基于发病机理的转化和 面向患者的研究以靶向潜在的HIV储藏并改善对残留感染的免疫控制。 此外，它们单独扩展并共同资助的计划，以实现长期指导 并为初级研究人员提供支持，以参与转化HIV治疗研究。