PROJECT SUMMARY: Lung diseases such as COPD, pulmonary hypertension, lung cancer and pneumonia are emerging as significant comorbidities in the HIV-infected population. even in the era of anti-retroviral therapy. Restoration of CD4 counts have seen a significant decline in incidences of microbial colonization of the lung by opportunistic pathogens. However pneumonia continues to be an important comorbidity in HIV infected patients. Recent studies show that the lower respiratory tract is a microbial reservoir in people living with HIV rather than being a sterile environment as observed in healthy non-infected subjects and these can serve as sources of infection. Similar microbial colonization of the airways is also observed in chronic airway diseases that are characterized by impaired mucociliary clearance (MCC) like Chronic obstructive pulmonary disease and Cystic fibrosis. Adequate MCC requires optimal ciliary beating and this depends on the maintenance of the airway surface liquid (ASL), a function of Cystic fibrosis transmembrane conductance regulator (CFTR) activity and the integrity of the signaling mechanism that regulates ciliary beating and fluid secretion. Impairment of either component of the MCC apparatus can compromise its efficacy. We have shown that TGF-?1 signaling, upregulated by tobacco smoke and crack cocaine abusers, can suppresses CFTR mRNA and this is not due to suppression of transcription from the CFTR promoter. We show that Human bronchial epithelial cells can be infected with HIV. We also show that cigarette smoke and HIV infection (Tat via TGF-? signaling) individually and additively suppress CFTR biogenesis and function. Aim 1 will determine mechanism by which Cigarette smoke and Tat (via TGF-? signaling) suppresses CFTR mRNA and function, and propose proof-of-concept experiments to restore CFTR biogenesis and function in the context of HIV and cigarette smoke. Aim 2 will test a novel therapeutic approach targeting the terminal step involved in establishing HIV latency to reactivate latent HIV from infected bronchial epithelial in presence of anti-retrovirals to eradicate viral reservoirs and decrease the Tat burden in the airway.