Mentored Scientist Award

Tuberculosis (TB) remains a major cause of morbidity and mortality for people living with HIV (PWH) worldwide, particularly in low-income settings. HIV and TB are both associated with increased rates of obstructive lung disease (OLD), with post-TB lung disease being an increasingly recognized entity associated with both pulmonary dysfunction and persistent respiratory symptoms. Sex-based differences have been found in TB prevalence, with men demonstrating higher rates of TB in multinational studies. However, whether there are sex-based differences in post-TB OLD among PWH is unknown. In this proposal, we will assess if there are sex-specific immune responses to TB disease driving post-TB OLD development in our Ugandan cohort. In our preliminary data, we found that among PWH sampled during active TB infection, women have lower markers of immune activation. This contrasts with the post-TB biomarker trend, which demonstrated elevated immune activation markers among women with HIV (WWH), consistent with other cohorts from sub-Saharan Africa and the US. We also found that WWH had a greater than four-fold higher odds of OLD compared to their male counterparts. Our findings that WWH have evidence of heightened immune activation and OLD risk than men with HIV but lower levels of immune activation during active TB suggest important sex-based differences in the TB immune response among PWH and may have important implications in the development of post-TB OLD. To assess if there are sex-specific mechanisms driving post-TB OLD risk, we will measure indolamine 2,3-dioxygenase (IDO) activity, a biomarker that has been found to measure TB disease activity among PWH and is elevated among WWH as compared to their male counterparts. We will measure IDO activity at the time of active TB and at completion of therapy. Spirometry and diffusing capacity will also be performed at completion of therapy, allowing us to evaluate if there are sex-based differences in IDO activity among HIV and TB co-infected individuals and whether IDO activity levels are associated with development of post-TB OLD. This is an important and timely study elucidating the role of sex on immune activation and the development of HIV-associated comorbidities. This will also provide important pilot data as I prepare my K23 application on sex-based differences in HIV-associated pulmonary disease.