The lung is an important reservoir of HIV and site of HIV replication, which results in virus-induced lung injury. How HIV leads to direct lung injury, and how virus replication is sustained within the lung, are not known. We found that HIV-infected lymphocytes induced fibroblasts to secrete fibronectin (FN), by elaboration of TGFbeta1, thus contributing to matrix remodeling. We also showed that matrix FN and a proteolytic fragment of FN,III1-C, enhanced HIV infection of lymphocytes and that FN-bound HIV remained infectious longer than unbound virus. We hypothesize that extracellular matrix, specifically fibronectin, enhances HIV infection within the lung and, conversely, that HIV within the lung increases proteolytic activity that contributes to inflammation and fibrosis. To test this we will: 1. Determine how matrix FN increases infectivity and stability of HIV. Interactions of matrix fibronectin and alveolar macrophages may contribute to persistent viral reservoir in the lung. 2. Define the matrix-degrading properties of HIV-infected cells. We hypothesize that HIV infection alters net protease activity, which results in matrix degradation and generation of biological active proteolytic fragments. 3. Determine the effect of HIV infection and HAART on protease activity of bronchoalveolar lavage fluid (BALF). HIV-induced protease activity may contribute to persistent infection and lung injury by generating proteolytic fragments of fibronectin that enhance infection, by cleaving natural inhibitors of HIV infection such as SDF-1alpha or by generating proteolytic fragments that directly cause lung injury. Therefore, we will measure proteolytic activity in BALF samples from HIV patients before and following HAART. 4. Develop a """"""""protein timeline"""""""" of HIV and HAART in the lung by identifying patterns of BALF protein expression over time using new methodologies in proteomics. Proteomic analysis may also identify new biomarkers of HIV-induced lung disease and reveal unsuspected pathways in HIV induced lung disease. These experiments will increase our understanding of the non-infectious complications of HIV infection in the lung, such as emphysema that involves matrix remodeling, and provide insight into consequences of HIV-induced proteolysis in the airspace environment.
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