JAC Advance Access originally published online on March 13, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 921-929
© 2003 The British Society for Antimicrobial Chemotherapy
Amelioration of nephropathy in mice expressing HIV-1 genes by the cyclin-dependent kinase inhibitor flavopiridol
1 Division of Nephrology, Box 1243, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; 2 Department of Pathology, Columbia University College of Physicians & Surgeons, New York, NY 10032; 3 Aventis Pharmaceuticals, Inc., Bridgewater, NJ 08807; 4 Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA
Received 2 October 2002; returned 20 December 2002; revised 10 January 2003; accepted 25 January 2003
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.
Keywords: kidney, renal, therapy, AIDS, model
* Corresponding author. Tel: +1-212-241-6155; Fax: +1-212-987-0389; E-mail: peter.nelson{at}mssm.edu
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