HIV nucleoside reverse transcriptase inhibitors efavirenz and tenofovir change the growth and differentiation of primary gingival epithelium

D. Mitchell, M. Israr, S. Alam, D. Dinello, J. Kishel, R. Jia, C. Meyers

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Objectives: 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.

Original languageEnglish (US)
Pages (from-to)196-202
Number of pages7
JournalHIV Medicine
Volume15
Issue number4
DOIs
StatePublished - Apr 2014

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Tenofovir
efavirenz
HIV Reverse Transcriptase
Reverse Transcriptase Inhibitors
Nucleosides
Epithelium
Growth
Pharmaceutical Preparations
Proliferating Cell Nuclear Antigen
Keratins
Keratin-6
HIV
Keratin-5
Differentiation Antigens
Highly Active Antiretroviral Therapy
Protease Inhibitors
Keratinocytes
HIV Infections
Cell Differentiation
Cell Cycle

All Science Journal Classification (ASJC) codes

  • Health Policy
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

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title = "HIV nucleoside reverse transcriptase inhibitors efavirenz and tenofovir change the growth and differentiation of primary gingival epithelium",
abstract = "Objectives: 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.",
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HIV nucleoside reverse transcriptase inhibitors efavirenz and tenofovir change the growth and differentiation of primary gingival epithelium. / Mitchell, D.; Israr, M.; Alam, S.; Dinello, D.; Kishel, J.; Jia, R.; Meyers, C.

In: HIV Medicine, Vol. 15, No. 4, 04.2014, p. 196-202.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HIV nucleoside reverse transcriptase inhibitors efavirenz and tenofovir change the growth and differentiation of primary gingival epithelium

AU - Mitchell, D.

AU - Israr, M.

AU - Alam, S.

AU - Dinello, D.

AU - Kishel, J.

AU - Jia, R.

AU - Meyers, C.

PY - 2014/4

Y1 - 2014/4

N2 - Objectives: 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.

AB - Objectives: 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.

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DO - 10.1111/hiv.12100

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