PATHOGENESIS OF HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV 1)

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The clinical syndrome associated with HIV-1 infection, AIDS, is dominated by immune deficiency resulting from CD4+ T-cell depletion and is manifested by recurrent infections with opportunistic organisms. Increasingly, however, several of the HIV-associated syndromes such as Kaposi's sarcoma, AIDS dementia complex, and HIV-associated nephropathy appear to be the result of a more direct effect of virus or viral proteins on host tissues. The objective of these studies is to explore the cellular and molecular mechanisms responsible for the generation of these HIV-associated diseases. In order to accomplish this objective, we have utilized a number of cellular and molecular biological approaches. We have created transgenic mouse lines expressing HIV genes in the absence of viral replication which develop an AIDS-like cachexia syndrome, psoriatic skin lesions, and renal disease. Evidence from these animals substantiates the important role of viral proteins in AIDS pathogenesis. As a result, we are investigating mechanism for the targeting of infected T-cells to specific host tissues. We have shown that T-cells infected with HIV-1 attach to fibronectin and that attachment is mediated by increased expression of a5b1 integrin on the cell surface. Once attached to the basement membrane, HIV-1 infected T-cells produce collagenase and invade artificial basement membranes. Current studies in the laboratory are directed to a better understanding of the specific viral proteins responsible for inducing these syndromes as well as the development of strategies for therapeutic intervention.