title: HIV nucleoside reverse transcriptase inhibitors efavirenz and tenofovir change the growth and differentiation of primary gingival epithelium.
abstract: OBJECTIVE
  An increasing number of HIV-infected patients are combating HIV infection through the use of antiretroviral drugs, including reverse transcriptase inhibitors. Oral complications associated with these drugs are becoming a mounting cause for concern. In our previous studies, both protease inhibitors and reverse transcriptase inhibitors have been shown to change the proliferation and differentiation state of oral tissues. This study examined the effect of a nonnucleoside and a nucleoside reverse transcriptase inhibitor on the growth and differentiation of gingival epithelium.
  
  
  METHODS
  Organotypic (raft) cultures of gingival keratinocytes were treated with a range of efavirenz and tenofovir concentrations. Raft cultures were immunohistochemically analysed to determine the effect of these drugs on the expression of key differentiation and proliferation markers, including cytokeratins and proliferating cell nuclear antigen (PCNA).
  
  
  RESULTS
  These drugs dramatically changed the proliferation and differentiation state of gingival tissues when they were present throughout the growth period of the raft tissue as well as when drugs were added to established tissue on day 8. Treatment with the drugs increased the expression of cytokeratin 10 and PCNA and, conversely, decreased expression of cytokeratin 5, involucrin and cytokeratin 6. Gingival tissue exhibited increased proliferation in the suprabasal layers, increased fragility, and an inability to heal itself.
  
  
  CONCLUSIONS
  Our results suggest that efavirenz and tenofovir treatments, even when applied in 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 be developed as a potential model for studying the effects of HIV and highly active antiretroviral therapy (HAART) in vitro.
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA, 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: D
authors.initials: D
authors.lastname: Dinello
authors.forename: J
authors.initials: J
authors.lastname: Kishel
authors.forename: R
authors.initials: R
authors.lastname: Jia
authors.forename: C
authors.initials: C
authors.lastname: Meyers
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005881:Gingiva / Q000166:cytology* / Q000187:drug effects; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006801:Humans; D053553:Keratin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D063065:Organophosphonates / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D000068698:Tenofovir
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D053553:Keratin-6; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine; C098320:efavirenz
keywords: HIV infections; antiretroviral therapy; cytokeratins; efavirenz; oral complications; tenofovir