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.
Highlights
Half of the people infected with HIV worldwide are women[1]
We found that concentrations of TFV-DP were 100-fold higher in epithelial cells and 10-fold higher in fibroblasts when compared to CD4+ T cells and macrophages
When epithelial cells were pre-loaded with TFV or tenofovir alafenamide (TAF), we found that both ARVs were released basolaterally for at least 3 days at concentrations that provide partial protection of CD4+ T cells from HIV infection, and that ARV release was partially due to Multidrug Resistant Protein (MRP) transporters
Summary
Half of the people infected with HIV worldwide are women[1]. In endemic areas like Sub-Sharan Africa women are at disproportionate increased risk for HIV acquisition compared to men, and HIV is the main cause of death for reproductive age women[2]. Sexual transmission is the main route for HIV acquisition in women, preventive strategies in women need to be effective in the female reproductive tract (FRT). Measured with sub-100-micron spatial resolution, the concentration of TFV following topical application was greatest in the epithelium and rapidly diminished deeper in the stroma. Taken together, these findings indicate a cell-specific distribution of TFV-DP in the reproductive tract and demonstrate that tissue biopsy concentrations may not reflect the physiologically-relevant concentrations of an ARV needed to prevent the sexual transmission of HIV. The recognition that ARVs are not uniformly distributed between cells in the reproductive tract emphasizes the need to understand the role of the tissue environment in modulating protection and susceptibility to HIV infection
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
