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 D1 and phospho-pRb (Ser780) expression, hallmarks of cyclin D1-mediated G1-->S phase progression.


RESULTS
We assessed cyclin D1 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 D1/cyclin-dependent kinase-4/6 known to promote G1-->S phase progression. HIV-1-infected podocytes showed markedly elevated cyclin D1 mRNA and cyclin D1 protein, the latter of which did not down-regulate during cell-cell contact or differentiation, suggesting post-transcriptional stabilization of cyclin D1 protein levels by HIV-1. The selective suppression of HIV-1 transcription by the cyclin-dependent kinase inhibitor, flavopiridol, abrogated cyclin D1 expression, underlying the requirement for HIV-1 encoded products to induce cyclin D1. Indeed, HIV-1 virus deleted of nef failed to induce cyclin D1 mRNA to the level of other single gene mutant viruses.


CONCLUSIONS
HIV-1 expression induces cyclin D1 and phospho-pRb (Ser780) expression in infected podocytes, suggesting that HIV-1 activates cyclin D1-dependent cell-cycle mechanisms to promote proliferation of infected renal epithelium.
Nelson
Peter J
PJ
Division of Nephrology, Mount Sinai School of Medicine, New York, NY 10029, USA. peter.nelson@mssm.edu
Sunamoto
Masaaki
M
Husain
Mohammad
M
Gelman
Irwin H
IH
D016263:AIDS-Associated Nephropathy / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000096:biosynthesis*; D016193:G1 Phase; D015497:HIV-1 / Q000502:physiology*; D051379:Mice; D010641:Phenotype; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase; D012694:Serine / Q000378:metabolism
D016160:Retinoblastoma Protein; D019938:Cyclin D1; D012694:Serine