The objective of these studies is to explore the role of extracellular matrix proteins and their receptors in the pathogenesis of AIDS. Recent work has focused on HIV-associated nephropathy which is increasingly recognized as a complication of infection with HIV-1, particularly among African Americans. Although the pathology has been well-characterized, the mechanisms by which HIV induces renal disease remains largely unknown. To address this issue, we have established a transgenic mouse model using HIV-1 proviral DNA rendered non-infectious by a 3 kb deletion overlapping the gag and pol genes. This construct contains the viral LTRs and encodes envelope glycoproteins as well as regulatory and accessory genes. Heterozygous mice develop renal disease essentially identical to HIV associated nephropathy in man with focal segmental glomerulosclerosis and tubulointerstitial disease. These findings support an important role for viral proteins in AIDS pathogenesis. As a result, we are currently exploring whether renal cells can sustain productive infection and how HIV-1 infected cells can target renal tissues. We have found that infected cells express surface adhesion molecules that recognize endothelium and basement membrane proteins. We have also found that T-cells and macrophages infected with HIV-1 express cell surface adhesion receptors, attach to basement membranes, and release proteases that facilitate tissue invasion. Current studies are directed to the development of new HIV-1 transgenic lines with single genes under the control of tissue-specific promoters, the testing of gene therapeutic constructs in our current transgenic lines, and new strategies for therapy including systemic antisense and HIV-1-targeted ribozymes.
