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.
Highlights
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
To examine the mechanisms involved in trauma-induced wound repair of the FRT mucosal barrier, which is essential for re-establishing homeostasis and suppressing mucosal inflammation, we developed an in vitro system using primary epithelial cells and stromal fibroblasts from the upper (endometrium (EM) and endocervix (CX)) and lower FRT (ectocervix (ECX))
In this study we demonstrate that high doses of TFV, equivalent to those used topically in HIV prevention trials, delay wound healing in response to mechanical injury of primary epithelial cells and fibroblasts from the human female reproductive tract
Summary
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. TAF had no inhibitory effect on wound closure or tight junction formation following injury. TFV but not TAF increased elafin and MIP3a secretion following injury, molecules known to be chemotactic for HIV-target cells. Young women aged 15–24 are most vulnerable to HIV infection, with sexual intercourse the predominant mechanism for HIV transmission. Clinical trials involving only women have been ineffective in preventing HIV acquisition, and showed lower concentrations of TFV in plasma[12,13]. Of three trials conducted in Africa to test the efficacy of topical TFV (CAPRISA 004, FACTS and VOICE), only CAPRISA 004 showed significant but moderate protection against HIV acquisition[12,14]. A major factor accounting for these mixed results[15], the contribution of other biological factors remains to be investigated
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