title: Human immunodeficiency virus-1 induces loss of contact inhibition in podocytes.
abstract: Human immunodeficiency virus-associated nephropathy (HIVAN) affects up to 10% of HIV-positive black adults and children and is the leading cause of renal disease in infected individuals. The disease is characterized by proliferation of renal epithelial cells, both glomerular and tubular. Diseased kidneys are enlarged, and glomerular visceral epithelial cells (podocytes) express proliferation markers. In a transgenic murine model of HIVAN expressing a deletion construct of HIV-1, the identical pathologic features are observed. It was demonstrated that HIV-1 mRNA is expressed in renal epithelium of the transgenic mouse and in patients with HIVAN, suggesting a direct role for HIV-1 in disease pathogenesis in both humans and the murine model. For investigating the mechanisms responsible for proliferative changes in podocytes, the HIV-1 transgenic mouse was bred onto the immortomouse background, and conditionally immortalized transgenic and nontransgenic podocyte cell lines were established. Transgenic podocytes demonstrated increased spontaneous proliferation, compared with nontransgenic podocytes at confluence, and they were found to have a greater percentage of cells in the proliferative phase of the cell cycle. It is striking that transgenic podocytes were not contact inhibited and formed aggregates in soft agar. Aggregates also formed when nontransgenic podocytes were infected with the identical HIV-1 construct used to generate the transgenic model. This demonstrates that the loss of contact inhibition is due to a direct effect of HIV-1. Therefore, proliferation induced by HIV-1 gene expression is likely to play a key role in the pathogenesis of HIVAN.
authors.affiliation: Division of Nephrology, Mount Sinai Medical Center, New York, New York.
authors.forename: Elissa J
authors.initials: EJ
authors.lastname: Schwartz
authors.affiliation: Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cara
authors.affiliation: Division of Gene Therapy, Mount Sinai Medical Center, New York, New York.
authors.forename: Hans
authors.initials: H
authors.lastname: Snoeck
authors.affiliation: Division of Nephrology, Mount Sinai Medical Center, New York, New York.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ross
authors.affiliation: Division of Nephrology, Mount Sinai Medical Center, New York, New York.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sunamoto
authors.affiliation: Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
authors.affiliation: Division of Nephrology, Mount Sinai Medical Center, New York, New York.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Klotman
mesh_terms: D000362:Agar / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers; D002450:Cell Communication / Q000502:physiology*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D003470:Culture Media / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015870:Gene Expression; D005814:Genes, Viral; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D013936:Thymidine / Q000378:metabolism
chemical_list: D015415:Biomarkers; D003470:Culture Media; D017077:Culture Media, Conditioned; D000362:Agar; D013936:Thymidine