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

• Published in: Journal of antimicrobial chemotherapy Vol. 51; no. 4; pp. 921 - 929
• Main Authors: Nelson, Peter J., D’Agati, Vivette D., Gries, Jean-Michel, Suarez, Jose-Ramon, Gelman, Irwin H.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2003; Oxford Publishing Limited (England)
• Subjects: AIDS; AIDS-Associated Nephropathy - drug therapy; AIDS-Associated Nephropathy - genetics; AIDS-Associated Nephropathy - pathology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; 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; Kidney - pathology; Kidney - virology; Medical sciences; Mice; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Piperidines - therapeutic use; renal; Reverse Transcriptase Polymerase Chain Reaction; therapy; Kidney disease; Immunopathology; Urinary system disease; HIV-1 virus; Rodentia; Retroviridae; AIDS; Immune deficiency; Lentivirus; Infection; Virus; In vivo; Vertebrata; Chemotherapy; Mammalia; Nephropathy; Treatment; Mouse; Viral disease; Animal; Inhibitor; Human immunodeficiency virus
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkg175

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.