Focal glomerulosclerosis in proviral and c-fms transgenic mice links Vpr expression to HIV-associated nephropathy.
Clinical and morphologic features of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN), such as proteinuria, sclerosing glomerulopathy, tubular degeneration, and interstitial disease, have been modeled in mice bearing an HIV proviral transgene rendered noninfectious through a deletion in gag/pol. Exploring the genetic basis of HIVAN, HIV transgenic mice bearing mutations in either or both of the accessory genes nef and vpr were created. Proteinuria and focal glomerulosclerosis (FGS) only developed in mice with an intact vpr gene. Transgenic mice bearing a simplified proviral DNA (encoding only Tat and Vpr) developed renal disease characterized by FGS in which Vpr protein was localized to glomerular and tubular epithelia by immunohistochemistry. The dual transgenic progeny of HIV[Tat/Vpr] mice bred to HIV[DeltaVpr] proviral transgenic mice displayed a more severe nephropathy with no apparent increase in Vpr expression, implying that multiple viral genes contribute to HIVAN. However, the unique contribution of macrophage-specific Vpr expression in the development of glomerular disease was underscored by the induction of FGS in multiple murine lines bearing a c-fms/vpr transgene.
Dickie
Peter
P
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. peter.dickie@ualberta.ca
Roberts
Amanda
A
Uwiera
Richard
R
Witmer
Jennifer
J
Sharma
Kirti
K
Kopp
Jeffrey B
JB
D016263:AIDS-Associated Nephropathy / Q000378:metabolism / Q000821:virology*; D000818:Animals; D004279:DNA, Viral / Q000032:analysis; D004198:Disease Susceptibility; D004848:Epithelium / Q000378:metabolism; D016336:Gene Products, vpr / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016236:Genes, fms; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011533:Proviruses / Q000235:genetics*; D014774:Virulence; D054325:vpr Gene Products, Human Immunodeficiency Virus
D004279:DNA, Viral; D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus