HIV-1 expression induces cyclin D1 expression and pRb phosphorylation in infected podocytes: cell-cycle mechanisms contributing to the proliferative phenotype in HIV-associated nephropathy

Background: The aberrant cell-cycle progression of HIV-1-infected kidney cells plays a major role in the pathogenesis of HIV-associated nephropathy, however the mechanisms whereby HIV-1 induces infected glomerular podocytes or infected tubular epithelium to exit quiescence are largely unknown. Here, we ask whether the expression of HIV-1 genes in infected podocytes induces cyclin D-1 and phospho-pRb (Ser780) expression, hallmarks of cyclin D1-mediated G(1) -> S phase progression. Results: We assessed cyclin D-1 and phospho-pRb (Ser780) expression in two well-characterized models of HIV-associated nephropathy pathogenesis: HIV-1 infection of cultured podocytes and HIV-1 transgenic mice (Tg26). Compared to controls, cultured podocytes expressing HIV-1 genes, and podocytes and tubular epithelium from hyperplastic nephrons in Tg26 kidneys, had increased levels of phospho-pRb (Ser780), a target of active cyclin D-1/cyclin-dependent kinase-4/6 known to promote G(1) -> S phase progression. HIV-1-infected podocytes showed markedly elevated cyclin D-1 mRNA and cyclin D-1 protein, the latter of which did not down-regulate during cell-cell contact or differentiation, suggesting post-transcriptional stabilization of cyclin D-1 protein levels by HIV-1. The selective suppression of HIV-1 transcription by the cyclin-dependent kinase inhibitor, flavopiridol, abrogated cyclin D-1 expression, underlying the requirement for HIV-1 encoded products to induce cyclin D-1. Indeed, HIV-1 virus deleted of nef failed to induce cyclin D-1 mRNA to the level of other single gene mutant viruses. Conclusions: HIV-1 expression induces cyclin D-1 and phospho-pRb (Ser780) expression in infected podocytes, suggesting that HIV-1 activates cyclin D-1-dependent cell-cycle mechanisms to promote proliferation of infected renal epithelium.