Glomerulosclerosis and viral gene expression in HIV-transgenic mice: role of nef.
BACKGROUND
Human immunodeficiency virus (HIV)-associated nephropathy is characterized by focal segmental glomerulosclerosis and microcystic tubular dilation. We have previously described a mouse transgenic for a Deltagag-pol HIV-1 genome, which develops glomerulosclerosis, cutaneous papillomas, and cataracts.


METHODS
We developed mice transgenic for a Deltagag-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 consistently manifested focal segmental glomerulosclerosis and tubular dilation by six weeks of age. Northern analysis indicated that renal transgene expression was higher in the Deltagag-pol-nef mice compared with the Deltagag-pol mice. In situ hybridization and immunostaining demonstrated HIV RNA and protein expression within the glomerular epithelial cells and tubular epithelial cells. These cell types showed histologic evidence of toxicity, including vacuolation and detachment from basement membrane, and exhibited increased rates of apoptosis. These data suggest that the renal disease seen in the Deltagag-pol-nef transgenic mouse may be caused by the expression of HIV genes within renal epithelial cells, that this expression may induce cellular toxicity, including apoptosis, and that nef is not required for the induction of renal disease. We have previously described mice bearing the nef gene, which do not manifest renal disease. In further experiments, Deltagag-pol-nef mice were bred with nef mice; these dual-transgenic mice developed renal disease that generally resembled that seen in Deltagag-pol-nef mice, but with somewhat more severe glomerulosclerosis and less severe tubulointerstitial injury.


RESULTS
The results of these transgenic studies suggest that the role of nef is complex and may act both to reduce transgene expression and to potentiate glomerular injury induced by other HIV-1 gene products.
Kajiyama
W
W
Kidney Disease Section, Metabolic Diseases Branch, NIDDK, and Imaging Facility, NIDR, NIH, Bethesda, Maryland, USA.
Kopp
J B
JB
Marinos
N J
NJ
Klotman
P E
PE
Dickie
P
P
D016263:AIDS-Associated Nephropathy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015152:Blotting, Northern; D005260:Female; D015967:Gene Expression Regulation, Viral; D015683:Gene Products, gag / Q000235:genetics; D015693:Gene Products, nef / Q000235:genetics*; D015684:Gene Products, pol / Q000235:genetics; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology / Q000503:physiopathology / Q000821:virology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D051437:Renal Insufficiency / Q000503:physiopathology / Q000821:virology; D019076:Transgenes / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus
D015683:Gene Products, gag; D015693:Gene Products, nef; D015684:Gene Products, pol; D015699:HIV Envelope Protein gp120; D012333:RNA, Messenger; D012367:RNA, Viral; D054311:nef Gene Products, Human Immunodeficiency Virus