title: Tenofovir Inhibits Wound Healing of Epithelial Cells and Fibroblasts from the Upper and Lower Human Female Reproductive Tract.
abstract: Disruption of the epithelium in the female reproductive tract (FRT) is hypothesized to increase HIV infection risk by interfering with barrier protection and facilitating HIV-target cell recruitment. Here we determined whether Tenofovir (TFV), used vaginally in HIV prevention trials, and Tenofovir alafenamide (TAF), an improved prodrug of TFV, interfere with wound healing in the human FRT. TFV treatment of primary epithelial cells and fibroblasts from the endometrium (EM), endocervix (CX) and ectocervix (ECX) significantly delayed wound closure. Reestablishment of tight junctions was compromised in EM and CX epithelial cells even after wound closure occurred. In contrast, TAF had no inhibitory effect on wound closure or tight junction formation following injury. TAF accumulated inside genital epithelial cells as TFV-DP, the active drug form. At elevated levels of TAF treatment to match TFV intracellular TFV-DP concentrations, both equally impaired barrier function, while wound closure was more sensitive to TFV. Furthermore, TFV but not TAF increased elafin and MIP3a secretion following injury, molecules known to be chemotactic for HIV-target cells. Our results highlight the need of evaluating antiretroviral effects on genital wound healing in future clinical trials. A possible link between delayed wound healing and increased risk of HIV acquisition deserves further investigation.
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756 USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Rodriguez-Garcia
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756 USA.
authors.forename: Mickey V
authors.initials: MV
authors.lastname: Patel
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756 USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756 USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Bodwell
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756 USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Rossoll
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756 USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Wira
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000187:drug effects / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D005836:Genitalia, Female / Q000187:drug effects / Q000473:pathology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D000068698:Tenofovir / Q000494:pharmacology*; D014621:Vagina / Q000187:drug effects / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D000068698:Tenofovir