Amelioration of nephropathy in mice expressing HIV-1 genes by the cyclin-dependent kinase inhibitor flavopiridol.
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.
Nelson
Peter J
PJ
Division of Nephrology, Box 1243, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. peter.nelson@mssm.edu
D'Agati
Vivette D
VD
Gries
Jean-Michel
JM
Suarez
Jose-Ramon
JR
Gelman
Irwin H
IH
D016263:AIDS-Associated Nephropathy / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005419:Flavonoids / Q000627:therapeutic use*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005814:Genes, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D007668:Kidney / Q000473:pathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010880:Piperidines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D018844:Cyclin-Dependent Kinases