Project Abstract/Summary People with HIV (PWH) have a high burden of respiratory symptoms due to chronic lung disease, of which COPD, diagnosed by spirometric obstruction on pulmonary function testing (PFT), is best studied. The most common finding on PFTs, however, is an abnormal diffusing capacity for carbon monoxide (DLco) with normal spirometry, or iso↓DLco. The clinical relevance of the iso↓DLco PFT phenotype is not known. Iso↓DLco is more common in PWH than in the general population, and HIV is an independent risk factor for reduced DLco. Preliminary work from our lab has shown that PWH with iso↓DLco have an increased respiratory symptom burden compared to PWH with normal PFTs. Iso↓DLco is also associated with a unique set of plasma inflammatory/immune biomarkers compared to other PFT phenotypes like spirometric obstruction, suggesting that the iso↓DLco PFT and biomarker pattern has a unique clinical correlate. The pathophysiology underlying this finding is not known but may be related to early structural lung disease (emphysema or interstitial lung disease) or pulmonary hypertension. Alternatively, iso↓DLco may be a sequela of chronic inflammation in the setting of long-standing HIV infection and possibly co-infection with other viruses like cytomegalovirus (CMV), which affect HIV persistence and immune activation. The central hypothesis for this study is that iso↓DLco is a unique HIV phenotype, possibly mediated by CMV-induced vasculopathy. The study will be nested within I AM OLD-DA, an established longitudinal cohort of PWH in San Francisco, USA and Kampala, Uganda, and will leverage the existing research infrastructure. In San Francisco we will use advanced imaging analyses of chest CTs to understand the etiology and potential causes of iso↓DLco. In Aim 1, we will evaluate CTs for emphysema, interstitial lung disease, pulmonary hypertension and air trapping; based on our pilot study, we expect that in about half of the PWH with iso↓DLco, imaging analysis will not identify a reason for the PFT finding. In Aim 3, we will test for association between iso↓DLco, CMV and distal pulmonary vascular remodeling (‘vascular pruning’) using quantitative CT methods with a working hypothesis that CMV-mediated vascular pruning is associated with iso↓DLco. In Kampala, Uganda, we will study a demographically and clinically distinct cohort or PWH and HIV-negative controls to determine the prevalence of iso↓DLco and its associated respiratory symptom burden (Aim 2). Altogether, the results from this study will help generate a deeper understanding of this PFT phenotype and determine if CMV is a modifiable risk factor for iso↓DLco and a target for therapeutic intervention. Completion of this project will also provide a platform for training Dr. Katerina Byanova, a pulmonary and critical care fellow at the University of California San Francisco, in the conduct of high-quality, patient-oriented clinical research. This grant will provide Dr. Byanova with the s...