Mentoring Scientists for Careers in HIV Translational Clinical Research

摘要/摘要 这个K24奖项的主要目标是确定和培养多样化的、高度上进的年轻调查人员。 具有独立思考的倾向，并增加他们对协作性的、以患者为中心的艾滋病毒的参与 病机及治疗研究。具体地说，初级调查人员将被指导从事创新 表征HIV全身持久性和确定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是 实施艾滋病毒治疗策略的能力有限，无法描述艾滋病毒在整个组织中的负担 抗逆转录病毒治疗的设置和监测相对于治疗干预的艾滋病毒蓄积物的变化。还有一个 缺乏关于这些微环境中的宿主免疫和遗传反应如何调节HIV的数据 持续或对病毒实施免疫控制而不使用抗逆转录病毒疗法。迫切需要新的方法来解决这个问题 在知识方面存在根本性差距，并开发评估治疗策略的工具。这项提案的目标是 目的是：(1)确定残留的艾滋病毒持久性与活动性、T细胞贩运和组织之间的关系 HIV治愈后表现出特殊精英控制或治疗后控制的PWH的药代动力学 治疗干预，(2)确定HIV bNAbs的纵向组织PK与ART和 在治愈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， 以及，(3)确定HIV组织负荷和残存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，并从感染艾滋病毒的猝死患者的组织中提取 艺术。这些目标涉及创新方法，例如艾滋病毒的磁共振成像研究 包膜特异性示踪剂89Zr-VRC01和[18F]-Arag，它被激活的T细胞选择性地摄取，并在 为识别多个HIV而定制的组织微环境的原位数字空间轮廓分析 代表艾滋病毒生命周期不同阶段的转录本与无偏见的人类转录组合 分析和靶向蛋白质组学。最终，这些研究将有助于指导清除艾滋病毒的干预性研究 并在停止抗逆转录病毒疗法后保持病毒免疫控制。这些目标代表了 首席研究员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，以潜在的艾滋病毒宿主为目标，改善对残余感染的免疫控制。 此外，他们还扩展了个人和合作资助的倡议，以实现长期指导 并支持初级调查人员参与转译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.