Human immunodeficiency virus-1 induces loss of contact inhibition in podocytes

Human immunodeficiency virus-associated nephropathy (HIVAN) affects up to 1 0% of HIV-positive black adults and children and is the leading cause of re nal disease in infected individuals. The disease is characterized by prolif eration of renal epithelial cells, both glomerular and tubular. Diseased ki dneys are enlarged, and glomerular visceral epithelial cells (podocytes) ex press proliferation markers. In a transgenic murine model of HIVAN expressi ng a deletion construct of HIV-1, the identical pathologic features are obs erved. It was demonstrated that HIV-1 mRNA is expressed in renal epithelium of the transgenic mouse and in patients with HIVAN, suggesting a direct ro le for HIV-1 in disease pathogenesis in both humans and the murine model. F or investigating the mechanisms responsible for proliferative changes in po docytes, the HIV-1 transgenic mouse was bred onto the immortomouse backgrou nd, and conditionally immortalized transgenic and nontransgenic podocyte ce ll lines were established. Transgenic podocytes demonstrated increased spon taneous proliferation, compared with nontransgenic podocytes at confluence, and they were found to have a greater percentage of cells in the prolifera tive phase of the cell cycle. It is striking that transgenic podocytes were not contact inhibited and formed aggregates in soft agar. Aggregates also formed when nontransgenic podocytes were infected with the identical HIV-1 construct used to generate the transgenic model. This demonstrates that the loss of contact inhibition is due to a direct effect of HIV-1. Therefore, proliferation induced by HIV-1 gene expression is likely to play a key role in the pathogenesis of HIVAN.