Mentoring the next generation of patient-oriented translational virologists

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY There is an urgent need for translational virologists and physician scientists, who are trained in translational patient-oriented research, have expertise across clinical/laboratory science, and can bridge the gaping divide that often occurs between purely clinical and laboratory-focused researchers. Translational HIV virologists are instrumental to the success of clinical trials networks, collaboratories, and for our goal to translate basic laboratory findings into novel therapeutics. However, it has become increasingly clear to me that the pipeline for translational HIV researchers has slowed to a trickle. The primary goal of this project will be to provide mentorship to trainees and early career investigators in clinical studies and cutting-edge translational virology techniques in key priority areas of HIV. Among the top priorities of the HIV field is the determination of the mechanisms behind HIV persistence, the search for therapeutic interventions that can lead to sustained antiretroviral therapy (ART)-free HIV post-treatment control, and the impact of HIV drug resistance to newer antiretroviral agents (ARVs). Trainees will have the opportunity to both lead and study participants from high- priority cohorts, such as the Low-V cohort of participants with non-suppressible viremia, the Control of HIV after Antiretroviral Medication Pause (CHAMP) study, the largest study of post-treatment controllers world- wide, and new HIV cure and treatment trials from the ACTG. This will be paired with training in cutting-edge laboratory techniques like the Matched Integration Site and Proviral Sequencing (MIP-Seq) and single-cell techniques for an in-depth analysis of the molecular circuits of HIV persistence and reservoir control. This is also an exciting time for HIV therapeutics with the rollout of dolutegravir in Africa and the introduction of long- acting injectables in the US. However, progress could be reversed with increasing drug resistance. We have developed robust next-generation sequencing platforms for HIV resistance sequencing and will use cohorts from the ACTG and sub-Saharan Africa to evaluate the prevalence and clinical impact of antiviral drug resistance mutations. Trainees will also have access to individualized training in virology, clinical trial design and implementation, biostatistics, and bioinformatics courses and co-mentors. With the successful completion of this project, we will have 1) trained the next generation of investigators to provide leadership and virology support for clinical studies focused on HIV; 2) advanced our understanding of the mechanisms of HIV persistence and control in PTCs, with implications for the design of HIV curative strategies for all individuals living with HIV, and 3) defined the impact of antiviral drug resistance and viral evolution to our newest ARVs.