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.