HIV-1 Vpr inhibits cytokinesis in human proximal tubule cells.
Transgenic mouse models of HIV-associated nephropathy (HIVAN) show that expression of HIV-1 genes in kidney cells produces collapsing focal segmental glomerulosclerosis and microcystic tubular disease typical of the human disease. HIV-1 vpr plays an important role in the glomerulosclerosis of HIVAN, especially when it is associated with nef expression in podocytes. Further, Vpr is reported to exacerbate tubular pathology. Here we determined effects of vpr expression on renal tubular epithelial cell function by transducing them with a pseudotyped lentivirus vector carrying HIV-1 vpr and control genes. Vpr expression in the cultured cells impaired cytokinesis causing cell enlargement and multinucleation. This profound in vitro phenotype caused us to reexamine the HIVAN mouse model and human HIVAN biopsies to see if similar changes occur in vivo. Both showed abundant hypertrophic tubule cells similar to the in vitro finding that represents a previously unappreciated aspect of the human disease. Additionally, multinucleated tubular cells were identified in the murine HIVAN model and increased chromosome number was detected in tubular cells of human HIVAN biopsies. Our study provides evidence of a new clinical phenotype in HIVAN that may result from the ability of Vpr to impair cytokinesis.
Rosenstiel
Paul E
PE
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. paul.rosenstiel@mssm.edu
Gruosso
Tina
T
Letourneau
Audrey M
AM
Chan
Justin J
JJ
LeBlanc
Amanda
A
Husain
Mohammad
M
Najfeld
Vesna
V
Planelles
Vicente
V
D'Agati
Vivette D
VD
Klotman
Mary E
ME
Klotman
Paul E
PE
D016263:AIDS-Associated Nephropathy / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D048749:Cytokinesis / Q000187:drug effects*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D016336:Gene Products, vpr / Q000235:genetics / Q000494:pharmacology*; D015726:Giant Cells / Q000821:virology; D015497:HIV-1; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000821:virology*; D051379:Mice; D014161:Transduction, Genetic
D016336:Gene Products, vpr; D054298:Human Immunodeficiency Virus Proteins