title: Effect of the HIV nucleoside reverse transcriptase inhibitor zidovudine on the growth and differentiation of primary gingival epithelium.
abstract: OBJECTIVE
  Oral complications associated with HIV infection and with the antiretroviral drugs used to treat it are of increasing concern in HIV-infected patients. Protease inhibitors have been shown to change the proliferation and differentiation state of oral tissues but the effect of nucleoside reverse transcriptase inhibitors is currently unknown. This study examined the effect of zidovudine on the growth and differentiation of the gingival epithelium.
  
  
  METHODS
  Gingival keratinocyte organotypic (raft) cultures were established. The raft cultures were treated with a range of zidovudine concentrations. Haematoxylin and eosin staining was performed to examine the effect of zidovudine on gingival epithelium growth and stratification. Raft cultures were immunohistochemically analysed to determine the effect of this drug on the expression of key differentiation and proliferation markers, including cytokeratins and proliferating cell nuclear antigen (PCNA).
  
  
  RESULTS
  Zidovudine dramatically changed the proliferation and differentiation state of gingival tissues both when it was present throughout the growth period of the tissue and when it was added to established tissue at day 8. Zidovudine treatment increased the expression of cytokeratin 10, PCNA and cyclin A. Conversely, cytokeratin 5, involucrin and cytokeratin 6 expression was decreased. The tissue exhibited characteristics of increased proliferation in the suprabasal layers as well as an increased fragility and an inability to heal itself.
  
  
  CONCLUSIONS
  Zidovudine treatment, even when applied at low concentrations for short periods of time, deregulated the cell cycle/proliferation and differentiation pathways, resulting in abnormal epithelial repair and proliferation. Our system could potentially be developed as a model for studying the effects of HIV and highly active antiretroviral therapy in vitro.
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mitchell
authors.forename: M
authors.initials: M
authors.lastname: Israr
authors.forename: S
authors.initials: S
authors.lastname: Alam
authors.forename: J
authors.initials: J
authors.lastname: Kishel
authors.forename: D
authors.initials: D
authors.lastname: Dinello
authors.forename: C
authors.initials: C
authors.lastname: Meyers
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D018809:Proliferating Cell Nuclear Antigen; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D007633:Keratins