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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.

SUBMITTER: Rodriguez-Garcia M

PROVIDER: S-EPMC5377941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recurrent spontaneous abortion (RSA) is a complex multifactorial disease. Recently, the microbiota of the female reproductive tract, as an emerging factor in RSA, has gradually attracted the attention of many clinical researchers. Here, we reported that the microbiota of the lower and upper female reproductive tracts from patients with RSA showed no significant differences in alpha diversity compared to that of controls. Beta diversity was significantly higher in the RSA group than in the control group in the vaginal microbiota (P = 0.036), cervical microbiota (P = 0.010) and microbiota from uterine lavage fluid (P = 0.001). In addition, dramatic decreases in gamma interferon and interleukin-6 cytokine levels were observed in the RSA group. In conclusion, our data suggested altered microbial biodiversity in the vagina, cervix and uterine lavage fluid in the RSA group. Alterations in the microbiota in the uterine cavity could be associated with altered cytokine levels, which might be a risk factor for RSA pathogenesis. Moreover, the microbiota composition differed markedly from the lower genital tract to the uterine cavity, and the microbiota in the uterine cavity also distinctly varied between endometrial tissue and uterine lavage fluid in the RSA group. Hence, sampling with these two methods simultaneously allowed a more comprehensive perspective of microbial colonization in the uterine cavity. IMPORTANCE As an obstacle to pregnancy, recurrent spontaneous abortion (RSA) can be caused by a variety of factors, and a current understanding of the etiology of RSA is still lacking; half of cases have an unknown cause. A substantial fraction of patients show no improvement after treatment. Since the microbiota of the female reproductive tract has been proposed as an emerging factor in RSA patients, further investigation is needed to provide guidance for clinical therapy. In general, this is the first report describing the distinct alterations of the vaginal, cervical, and uterine microbiota in RSA, not just that in the vagina. Furthermore, another major strength of this study derived from the further in-depth investigation and analysis of the characteristics of the microbiota colonizing the upper female genital tract in RSA, which provided a more comprehensive view for investigating the uterine microbiota.

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Tenofovir Inhibits Wound Healing of Epithelial Cells and Fibroblasts from the Upper and Lower Human Female Reproductive Tract.

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