Glomerulosclerosis and viral gene expression in HIV-transgenic mice: Role of nef

Background. Human immunodeficiency virus (HIV)-associated nephropathy is ch aracterized by focal segmental glomerulosclerosis and microcystic tubular d ilation. We have previously described a mouse transgenic for a Delta gag-po l HIV-1 genome, which develops glomerulosclerosis, cutaneous papillomas, an d cataracts. Methods. We developed mice transgenic for a Delta gag-pol-nef HIV genome in order to investigate the role of the nef gene in these phenotypes. Results. One transgenic line, X5, expressed HIV mRNA in kidney and consiste ntly manifested focal segmental glomerulosclerosis and tubular dilation by six weeks of age. Northern analysis indicated that renal transgene expressi on was higher in the Delta gag-pol-nef mice compared with the Delta gag-pol mice. In situ hybridization and immunostaining demonstrated HIV RNA and pr otein expression within the glomerular epithelial cells and tubular epithel ial cells. These cell types showed histologic evidence of toxicity, includi ng vacuolation and detachment from basement membrane, and exhibited increas ed rates of apoptosis. These data suggest that the renal disease seen in th e Delta gag-pol-nef transgenic mouse may be caused by the expression of HIV genes within renal epithelial cells, that this expression may induce cellu lar toxicity, including apoptosis, and that nef is not required for the ind uction of renal disease. We have previously described mice bearing the nef gene, which do not manifest renal disease. In further experiments, Delta ga g-pol-nef mice were bred with nef mice; these dual-transgenic mice develope d renal disease that generally resembled that seen in Delta gag-pol-nef mic e, but with somewhat more severe glomerulosclerosis and less severe tubuloi nterstitial injury. Results. The results of these transgenic studies suggest that the role of n ef is complex and may act both to reduce transgene expression and to potent iate glomerular injury induced by other HIV-1 gene products.