While the epidemiologic data linking HIV infection to an increased risk for COPD is clear, the pathogenesis of the accelerated development of COPD in HIV infected smokers is not understood. We have focused on the SAE as the central target for the accelerated development of COPD in HIV infected smokers, as there is extensive data pointing to the SAE as the initial site of lung pathology in cigarette smokers and the small airways are the major site of airflow obstruction in COPD. Further, the emphysema associated with COPD begins in alveoli surrounding the SAE, and prior to the development of clinical evidence of lung disease, the SAE of smokers exhibit marked disordered biology, including changes in DNA methylation and gene expression, and disordered differentiation. Importantly, we have observed that HIV infection "ages" the SAE, with exaggerated shortening of SAE telomeres in individuals infected with HIV compared to HIV ‾ smokers.