PROJECT SUMMARY Through this K23 award, the candidate, an infectious disease physician with advanced training in tuberculosis (TB) and global TB/HIV research, will become an independent physician-scientist bridging clinical and molecular epidemiology and drug-resistance genomics. The candidate’s long-term goal is to improve our understanding of the relationship between HIV, drug-resistant TB mutations, TB transmission and clinical outcomes in order to better target interventions and guide treatment. To meet these goals, the candidate requires: 1) Skills in the analysis of large clinical cohorts; 2) Fluency with existing molecular epidemiology analysis and modelling; 3) Working knowledge of next generation sequencing techniques and analysis pipelines; 4) Experience in the recruitment and management of prospective clinical cohorts; 5) Professional development and preparation for extramural funding. This K23 outlines a 5-year plan of coursework, hands on training, and assembles a multidisciplinary mentorship team to address these competencies. Dr. Karen Jacobson (primary mentor) has over 10 years’ experience conducting international tuberculosis studies and a successful NIH-funded grant portfolio. Prof. Robin Warren and Dr. David Engelthaler (co-mentors) are experts in Mycobacterium tuberculosis drug resistance and next generation sequencing techniques, respectively. Drs. C. Robert Horsburgh and Laura White (advisors), together with Prof. Helen Cox (advisor) will provide clinical and molecular epidemiology expertise along with biostatistical modelling support. This K23 will address our lack of understanding of the association between HIV and rifampin-resistant/multidrug-resistant TB (RR/MDR- TB). The candidate will leverage a bank of RR/MDR-TB specimens from the Western Cape Province, South Africa, to examine how transmitted and acquired TB drug resistance varies over a twelve-year period among people living with and without HIV (aim 1). Next, the role of TB drug-resistance compensating mutations in RR/MDR-TB transmission at the community-level will be examined in a retrospective cohort in Worcester, South Africa, including the impact of HIV and other risk factors (aim 2). Finally, in a prospective pilot cohort, whole genome and next generation sequencing techniques will be used to examine whether TB drug resistance evolves differently during TB treatment in people with and without HIV, and in those presenting on and off antiretroviral therapy in Worcester, South Africa (aim 3). Knowledge gained from this study will translate into interventions to decrease the risk of RR/MDR-TB infection and improve long-term outcomes for people with HIV. By building upon her prior research experience and training, utilizing the biobank of RR/MDR-TB specimens and a well-established research site, along with methodologic training and expert mentorship, the candidate is well positioned to accomplish the proposed training and research aims and to then apply for an R01 ...