HIV-1 infection is characterized by the gradual loss of the cell-mediated immune response and the ultimate development of opportunistic infections and neoplasms. In addition, patients infected with HIV-1 manifest a number of debilitating inflammatory conditions of the CNS, lung, gastrointestinal tract, skeletal muscle, skin, heart, and joints. Excluding inflammation secondary to opportunistic infections, these inflammatory conditions are believed to represent primary lentiviral-induced lesions. However, the viral and host parameters and pathogenetic mechanisms responsible for the development of these inflammatory conditions are not known. Multiple lines of evidence indicate that inflammatory reactions are modulated by leukocyte interactions with adhesion molecules on endothelial cell membranes. The work outlined in this proposal focuses on the hypothesis that AIDS-related inflammatory disease occurs as a direct result of changes in the adhesive interactions between endothelium and circulating leukocytes. Specifically, to test this hypothesis and to explore the mechanisms involved in the evolution of AIDS-related inflammatory disease, we plan to use the SIVmac model to: 1) examine the viral determinants associated with inflammatory disease in AIDS, 2) determine the relative expression of endothelial-derived leukocyte adhesion molecules in tissues from SIVmac-infected monkeys using immunohistochemical techniques, 3) examine leukocyte-endothelial adhesion in AIDS by determining the immunophenotypes of leukocytes and adhesion molecules involved in AIDS-related inflammatory disease using multiple in vitro and in vivo techniques, 4) investigate the mechanisms responsible for any changes in endothelial adhesion expression in tissues from SIVmac-infected animals by examining these tissues for cytokine elaboration and by examining normal rhesus endothelial cells for adhesion molecule expression after coculturing with SIVmac-infected cells, supernatants, or whole virus, and 5) investigate the roles of other factors in leukocyte extravasation in AIDS by examining vessels for evidence of reductions in flow caliber and for the presence of specific chemotactic factors.
