PROJECT SUMMARY/ABSTRACT People living with HIV (PLWH) are at heightened risk for chronic lung diseases. The mechanisms underlying this risk are poorly understood. Viral infections are major causes of acute respiratory events including pneumonia as well as asthma and COPD exacerbations, all of which can increase the risk of chronic lung impairments. The nasal mucosal “secretome”, composed of cytokines/chemokines and other soluble mediators, limits the initial spread of viral infections through controlling viral entry, releasing cytokines/chemokines, as well as numerous immune modulating mediators. The nasal microbiome, including bacterial microbiome and fungal mycobiome, is a critical component of the respiratory immune system, acting as a barrier against harmful pathogens Our research group has established approaches to rigorously characterize and quantify the nasal mucosal secretome and microbiome. Our overall objective is to determine nasal mucosal immune and microbiome alterations and clinical implications associated with these changes among PLWH compared to seronegative individuals. We hypothesize that alteration of the nasal mucosal milieu among PLWH is associated with adverse pulmonary outcomes. We will characterize the nasal immune environment (Aim 1) and microbiome (Aim 2) of PLWH compared to seronegative individuals. Through longitudinal assessments embedded in these Aims we will define the variability in these measures. We will then define nasal mucosal endotypes associated with pulmonary consequences among PLWH compared with seronegative MWCCS participants (Aim 3). Successful completion of these aims will lead to a rigorous characterization of the nasal mucosal and microbiome changes among PLWH, identifying potential endotypes associated with adverse pulmonary outcomes in this population. These results will provide valuable insights to guide therapeutic strategies and interventions to modify nasal mucosal inflammation and nasal microbiome and its associated complications in this vulnerable population.