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 sugges ts that HIV-1 gene expression induces these changes. Flavopiridol and rosco vitine, 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 prolif eration and a return to the differentiated phenotype. Dose-response analysi s showed that both flavopiridol and roscovitine reversibly suppressed HIV-1 transcription in podocytes in vitro at an IC50 of 25 nM and 3 muM, respect ively. Despite equivalent suppression of HIV-1 transcription, roscovitine w as a more effective inhibitor of podocyte proliferation than flavopiridol. Suppression of HIV-1 transcription by flavopiridol or roscovitine was marke d by re-expression of the podocyte differentiation markers, synaptopodin an d podocalyxin. These results suggest that inhibition of HIV-1 transcription decreases podocyte proliferation and permits the reexpression of different iation markers. Thus, suppression of HIV-1 transcription by selective cycli n-dependent kinase-9 inhibitors may be a useful therapeutic strategy for th e treatment of HIVAN.