Amelioration of nephropathy in mice expressing HIV-1 genes by the cyclin-dependent kinase inhibitor flavopiridol

J Antimicrob Chemother. 2003 Apr;51(4):921-9. doi: 10.1093/jac/dkg175. Epub 2003 Mar 13.


Cumulative evidence suggests that human immunodeficiency virus-associated nephropathy (HIVAN), the third leading cause of end-stage renal disease in African-Americans, may respond to therapeutic strategies that interrupt HIV-1 expression in infected renal epithelium. We recently demonstrated that suppression of HIV-1 transcription in infected glomerular visceral epithelial cells by flavopiridol, a small-molecule inhibitor of the cyclin-dependent kinases required for HIV-1 promoter activity, reversed HIV-induced proliferation and dedifferentiation in vitro. To address whether flavopiridol could ameliorate HIV-induced renal disease, we utilized a well-established HIV-1 NL4-3 transgenic mouse model of HIVAN. HIV-1 proviral transgene expression in whole kidney was markedly suppressed by a 20 day treatment with flavopiridol. Following treatment, histopathological, serological and urinary indices of nephrosis were normalized in flavopiridol-treated but not in vehicle-treated transgenics. Microarray analysis showed that 82% of the dysregulated genes in HIVAN kidney were normalized to control levels by flavopiridol, whereas continued dysregulation of most of the remaining 18% was attributable to an effect from flavopiridol alone. These results demonstrate for the first time that targeting the cyclin-dependent kinases that support HIV-1 expression can ameliorate HIV-induced disease in an animal model.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • AIDS-Associated Nephropathy / drug therapy*
  • AIDS-Associated Nephropathy / genetics
  • AIDS-Associated Nephropathy / pathology
  • Animals
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Enzyme Inhibitors / therapeutic use*
  • Flavonoids / therapeutic use*
  • Gene Expression Regulation, Viral / drug effects
  • Genes, Viral / drug effects
  • HIV-1 / drug effects
  • HIV-1 / genetics*
  • Kidney / pathology
  • Kidney / virology
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Piperidines / therapeutic use*
  • Reverse Transcriptase Polymerase Chain Reaction


  • Enzyme Inhibitors
  • Flavonoids
  • Piperidines
  • alvocidib
  • Cyclin-Dependent Kinases