PATHOGENESIS OF HUMAN IMMUNODEFICIENCY VIRUS 1

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Patients infected with human immunodeficiency virus type 1 (HIV-1) develop a syndrome of cachexia and wasting associated with recurrent infections with opportunistic organisms, thought to be the result of CD4+ T-cell depletion. In addition, patients develop tissue-specific syndromes that may be more directly related to interactions of the host tissues with replicating virus or viral gene products such as Kaposi's Sarcoma, AIDS dementia complex, cutaneous disorders associated with AIDS, and HIV-associated nephropathy. The objective of these studies is to explore the cellular and molecular mechanisms responsible for the the generation of these HIV-associated diseases. To explore the role of viral gene products in the absence of replicating virus, we have created transgenic mice using a non-infectious HIV-1 proviral construct lacking the gag and pol genes but encoding env, and the accessory genes tat, rev, vif, vpr, and vpu. In the F2 generation, homozygous affected animals develop growth retardation, skin lesions, lymphoid hyperplasia, thymic involution, splenomegaly, profound wasting, and early death by day 25. Heterozygous animals appear phenotypically normal at birth but approximately 60% develop renal disease within 200 days of life. The majority of heterozygous animals also develop epidermal papillomatous lesions (60%) and a rare myopathy associated with weight loss and wasting (2%). These studies substantiate an important role for viral proteins in AIDS pathogenesis. As a result, we are investigating mechanisms for the targeting of injected 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 alpha5beta1 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. New development of strategies for therapeutic intervention. New transgenic mice are being generated that target HIV genes to specific sites. These studies are intended to explore HIV pathogenesis and to to develop novel therapeutic strategies directed at the prevention of HIV associated syndrome.