Suppression of HIV-1 expression by inhibitors of cyclin-dependent kinases promotes differentiation of infected podocytes.
The glomerular lesions of HIV-associated nephropathy (HIVAN) are associated with the expression of HIV-1 in podocytes. Infected podocytes proliferate and lose several differentiation markers in vivo and in vitro, which suggests that HIV-1 gene expression induces these changes. Flavopiridol and roscovitine, newly identified inhibitors of cyclin-dependent kinase-9, markedly decrease HIV-1 promoter activity in cell lines of various lineages. In this study, the inhibitors were used to determine whether suppression of HIV-1 transcription in infected podocytes correlated with an inhibition of proliferation and a return to the differentiated phenotype. Dose-response analysis showed that both flavopiridol and roscovitine reversibly suppressed HIV-1 transcription in podocytes in vitro at an IC(50) of 25 nM and 3 microM, respectively. Despite equivalent suppression of HIV-1 transcription, roscovitine was a more effective inhibitor of podocyte proliferation than flavopiridol. Suppression of HIV-1 transcription by flavopiridol or roscovitine was marked by re-expression of the podocyte differentiation markers, synaptopodin and podocalyxin. These results suggest that inhibition of HIV-1 transcription decreases podocyte proliferation and permits the reexpression of differentiation markers. Thus, suppression of HIV-1 transcription by selective cyclin-dependent kinase-9 inhibitors may be a useful therapeutic strategy for the treatment of HIVAN.
Nelson
Peter J
PJ
Divisions of *Nephrology and †Infectious Diseases, Mount Sinai School of Medicine, New York, New York.
Gelman
Irwin H
IH
Divisions of *Nephrology and †Infectious Diseases, Mount Sinai School of Medicine, New York, New York.
Klotman
Paul E
PE
Divisions of *Nephrology and †Infectious Diseases, Mount Sinai School of Medicine, New York, New York.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005419:Flavonoids / Q000627:therapeutic use*; D005814:Genes, Viral / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D015497:HIV-1 / Q000235:genetics; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D051379:Mice; D010880:Piperidines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*; D000077546:Roscovitine; D014158:Transcription, Genetic / Q000187:drug effects
D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D011687:Purines; D000077546:Roscovitine; C077990:alvocidib; D018844:Cyclin-Dependent Kinases