Epithelial Cells and Fibroblasts from the Human Female Reproductive Tract Accumulate and Release TFV and TAF to Sustain Inhibition of HIV Infection of CD4+ T cells

Sci Rep. 2019 Feb 12;9(1):1864. doi: 10.1038/s41598-018-38205-y.

Abstract

Tenofovir (TFV) treatment of female reproductive tract (FRT) cells results in differential accumulation of intracellular Tenofovir diphosphate (TFV-DP) in different cell types, with greater concentrations in epithelial cells (100-fold) and fibroblasts (10-fold) than in CD4+ T cells. The possibility that TFV-DP accumulation and retention in epithelial cells and fibroblasts may alter TFV availability and protection of CD4+ T cells against HIV infection, prompted us to evaluate TFV and/or Tenofovir alafenamide (TAF) release from FRT cells. Endometrial, endocervical and ectocervical polarized epithelial cells and fibroblasts were pre-loaded with TFV or TAF, and secretions tested for their ability to inhibit HIV infection of activated blood CD4+ T cells. Epithelial cell basolateral secretions (1, 2 and 3 days post-loading), but not apical secretions, suppressed HIV infection of CD4+ T cells, as did secretions from pre-loaded fibroblasts from each site. Intracellular TFV-DP levels in epithelial cells following preloading with TFV or TAF correlated directly with ARV protection of CD4+ T cells from HIV infection. When added apically to epithelial cells, TFV/TAF was released basolaterally, in part through Multidrug Resistant Protein transporters, taken up by fibroblasts and released into secretions to partially protect CD4+ T cells. These findings demonstrate that epithelial cells and fibroblasts release TFV/TAF for use by CD4+ T cells and suggest that the tissue environment plays a major role in the sustained protection against HIV infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacokinetics
  • Adult
  • Anti-HIV Agents / pharmacokinetics*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / virology*
  • Cervix Uteri / drug effects
  • Cervix Uteri / virology
  • Drug Resistance, Multiple
  • Endometrium / drug effects
  • Endometrium / virology
  • Epithelial Cells / drug effects*
  • Female
  • Fibroblasts / drug effects*
  • Genitalia, Female / cytology*
  • Genitalia, Female / drug effects
  • Genitalia, Female / virology
  • HIV Infections / prevention & control*
  • Humans
  • Middle Aged
  • Organophosphates / pharmacokinetics
  • Vagina / drug effects
  • Vagina / virology

Substances

  • Anti-HIV Agents
  • Organophosphates
  • tenofovir diphosphate
  • tenofovir alafenamide
  • Adenine