PROJECT SUMMARY:Lung diseases such as COPD, pulmonary hypertension, lung cancer and pneumonia are emerging assignificant comorbidities in the HIV-infected population. even in the era of anti-retroviral therapy. Restoration ofCD4 counts have seen a significant decline in incidences of microbial colonization of the lung by opportunisticpathogens. However pneumonia continues to be an important comorbidity in HIV infected patients. Recentstudies show that the lower respiratory tract is a microbial reservoir in people living with HIV rather than beinga 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 characterizedby 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 surfaceliquid (ASL), a function of Cystic fibrosis transmembrane conductance regulator (CFTR) activity and theintegrity of the signaling mechanism that regulates ciliary beating and fluid secretion. Impairment of eithercomponent 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 tosuppression of transcription from the CFTR promoter. We show that Human bronchial epithelial cells can beinfected with HIV. We also show that cigarette smoke and HIV infection (Tat via TGF- signaling) individuallyand additively suppress CFTR biogenesis and function. Aim 1 will determine mechanism by which Cigarettesmoke and Tat (via TGF- signaling) suppresses CFTR mRNA and function, and propose proof-of-conceptexperiments to restore CFTR biogenesis and function in the context of HIV and cigarette smoke. Aim 2 will testa novel therapeutic approach targeting the terminal step involved in establishing HIV latency to reactivatelatent HIV from infected bronchial epithelial in presence of anti-retrovirals to eradicate viral reservoirs anddecrease the Tat burden in the airway.