Abstract
The conflicting results of recent pre-exposure prophylaxis (PrEP) trials utilizing tenofovir (TFV) to prevent HIV infection in women led us to evaluate the accumulation of intracellular TFV-diphosphate (TFV-DP) in cells from the female reproductive tract (FRT) and whether sex hormones influence the presence of TFV-DP in these cells. Following incubation with TFV, isolated epithelial cells, fibroblasts, CD4+ T cells and CD14+ cells from the FRT as well as blood CD4+ T cells and monocyte-derived macrophages convert TFV to TFV-DP. Unexpectedly, we found that TFV-DP concentrations (fmol/million cells) vary significantly with the cell type analyzed and the site within the FRT. Epithelial cells had 5-fold higher TFV-DP concentrations than fibroblasts; endometrial epithelial cells had higher TFV-DP concentrations than cells from the ectocervix. Epithelial cells had 125-fold higher TFV-DP concentrations than FRT CD4+ T cells, which were comparable to that measured in peripheral blood CD4+ T cells. These findings suggest the existence of a TFV-DP gradient in the FRT where epithelial cells > fibroblasts > CD4+ T cells and macrophages. In other studies, estradiol increased TFV-DP concentrations in endometrial and endocervical/ectocervical epithelial cells, but had no effect on fibroblasts or CD4+ T cells from FRT tissues. In contrast, progesterone alone and in combination with estradiol decreased TFV-DP concentrations in FRT CD4+ T cells. Our results suggest that epithelial cells and fibroblasts are a repository of TFV-DP that is under hormonal control. These cells might act either as a sink to decrease TFV availability to CD4+ T cells and macrophages in the FRT, or upon conversion of TFV-DP to TFV increase TFV availability to HIV-target cells. In summary, these results indicate that intracellular TFV-DP varies with cell type and location in the FRT and demonstrate that estradiol and/or progesterone regulate the intracellular concentrations of TFV-DP in FRT epithelial cells and CD4+ T cells.
Highlights
The Human Immunodeficiency Virus (HIV) global pandemic has become one of the world’s most serious health challenges
In other studies, we found that 100 K cells and 1 mg/ml TFV was optimal for measuring TFV-DP in blood monocyte-derived macrophages
In the present study we demonstrate that immune and nonimmune cells from the human female reproductive tract (FRT) take up TFV and activate it to TFV-DP, the active form that inhibits reverse transcriptase to block HIV infection of target cells
Summary
The Human Immunodeficiency Virus (HIV) global pandemic has become one of the world’s most serious health challenges. There were 35.3 million people living with HIV at the end of 2012 and about 2.3 million new infections during 2012 [1]. The majority of new cases are spread by vaginal and anal sexual intercourse, with a higher proportion of women infected via heterosexual intercourse than men [2]. The female reproductive tract (FRT) is the primary mucosal site of infection by STDs including HIV. The FRT is exposed to large fluxes in the levels of the sex hormones estradiol (E2) and progesterone (P4) across the menstrual cycle, and at concentrations higher than those observed elsewhere in the body. Sex hormone modulation of innate and adaptive immune protection led to the hypothesis of a ‘‘Window of Vulnerability’’
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