Mentoring Scientists for Careers in HIV Translational Clinical Research

摘要/总结 这个K24奖项的主要目标是识别和培养多样化，积极性高，年轻的研究人员 有独立思考倾向的人，并增加他们参与协作，以病人为导向的艾滋病毒 发病机理及治疗研究。具体而言，初级调查员将被指导从事创新的 表征全身HIV持续性和确定HIV宿主控制机制的方法 感染;研究将促进他们的学术生涯。成功设计的主要障碍之一， 艾滋病毒治疗策略的实施是有限的能力来表征艾滋病毒的组织范围的负担， ART的设置和监测HIV宿主相对于治疗干预的变化。还有一个 缺乏关于这些微环境中宿主免疫和遗传反应如何调节HIV的数据 因此，迫切需要新的方法来解决这一问题 这是一个重大的知识差距，并开发工具来评估治疗战略。本提案的目标 目的是：（1）确定残留艾滋病毒持续性和活性、T细胞运输和组织之间的关系 在HIV治疗后表现出特殊的精英控制或治疗后控制的PWH中的药代动力学 治疗干预，（2）确定HIV bnAb、ART和 在治疗干预的背景下使用免疫PET成像和淋巴结微透析的病毒动力学， 和（3）确定HIV组织负荷和残余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，并取自艾滋病毒猝死受害者的组织 条这些目标涉及创新的方法，如艾滋病毒的磁共振成像研究， 细胞特异性示踪剂，89 Zr-VRC 01和[18F]F-AraG，其被活化的T细胞选择性地摄取，并且在 组织微环境的原位数字空间轮廓分析，其已定制以识别多种HIV 代表HIV生命周期各个阶段的转录物与无偏倚的人类转录组学相结合， 分析和靶向蛋白质组学。最终，这些研究将有助于指导干预性研究，以清除艾滋病毒 停止抗逆转录病毒治疗后，维持病毒免疫控制。 主要研究者的合作研究计划结合了基于发病机制的翻译和 以患者为导向的研究，以潜伏的艾滋病毒宿主为目标，提高对残余感染的免疫控制。 此外，他们还扩大了单独和合作资助的举措，以实现长期的指导 并为初级研究人员提供参与转化型艾滋病毒治疗研究的机会。

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.