PROJECT SUMMARY/ABSTRACT Background: One in four people living with COPD – 96 million people worldwide – have never smoked. Most COPD mortality occurs in regions of the world where smoking is uncommon, like sub-Saharan Africa, where HIV and air pollution may be driving COPD mortality among the estimated 26 million Africans with COPD. People living with HIV (PLWH) experience persistent systemic inflammation and increased risk of chronic lung disease. Like HIV, air pollution – the leading environmental cause of death globally – causes systemic inflammation and significantly worsens lung health. HIV and air pollution operate through similar inflammatory pathways that are destructive to lung tissues. Thus, PLWH who are exposed to air pollution may face particularly high risk of lung disease. If shared inflammatory pathways accentuate lung disease risk among PLWH exposed to air pollution, then targeting these pathways could have outsized clinical impact. The hypothesis of this project is that PLWH experience greater air pollution-associated lung inflammation and lung dysfunction than HIV-uninfected people. I helped establish a four-year collaboration between Massachusetts General Hospital, Mbarara University of Science and Technology, and Harvard T.H. Chan School of Public Health that has enabled air quality monitoring in southwestern Uganda and is poised to investigate this novel area of research. Candidate: Dr. North's overarching career goal is to become an independent investigator focused on environmental exposures and lung health among PLWH. Her clinical work caring for patients with chronic lung disease and leading research investigating the epidemiology of chronic lung disease in Uganda have inspired this career path. She is well- prepared to undertake the scientific and training aims proposed here, having successfully published eight first- author manuscripts, three middle-author manuscripts, and completed a 2016 pilot study of air quality in rural Uganda. Mentoring: Dr. Mark Siedner (Primary mentor) is an NIH-funded investigator who has successfully mentored 4 NIH K awardees. Drs. Petros Koutrakis (personal air pollution measurement), Bethany Hedt-Gauthier (biostatistics), and Benjamin Medoff (immune-mediated lung injury), will provide additional focused mentoring to ensure Dr. North's success. Research: Leveraging an ongoing, R01-funded cohort of 300 HIV-infected and 300 age- and sex-similar, HIV-uninfected participants, Dr. North will add personal air pollution monitoring and research bronchoscopy to ongoing study procedures in order to characterize personal air pollution exposure and examine relationships between air pollution, lung inflammation and lung function. Training: To achieve her aims and become an independent researcher, Dr. North requires additional training in 1) personal air pollution measurement, 2) advanced biostatistics including structural equation modeling, and 3) immune-mediated lung injury. Based on her previous research experience, expanding publication record, exceptional mentoring team, strong institutional commitment, and innovative research plan, Dr. North is well-positioned to become an independent clinical investigator focused on environmental exposures and lung health among PLWH.

PROJECT NARRATIVE Most global COPD morality occurs in regions of the world where smoking is uncommon such as sub-Saharan Africa – home to an estimated 26 million people with COPD – where the converging HIV and air pollution epidemics may be driving COPD mortality. This project characterizes personal air pollution exposure among 300 people with HIV and 300 HIV-uninfected comparators in Uganda and uses spirometry and research bronchoscopy to examine whether HIV serostatus influences relationships between air pollution, inflammation and lung function. Findings from this study will inform future interventions designed to improve lung health among these at-risk populations by targeting the candidate mechanistic pathways identified in this proposal.