title: Sex hormones regulate tenofovir-diphosphate in female reproductive tract cells in culture.
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.
authors: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors: Zheng
authors: Z
authors: Shen
authors: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors: John V
authors: JV
authors: Fahey
authors: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors: Jack E
authors: JE
authors: Bodwell
authors: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors: Marta
authors: M
authors: Rodriguez-Garcia
authors: Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina, United States of America.
authors: Angela D M
authors: AD
authors: Kashuba
authors: Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors: Charles R
authors: CR
authors: Wira
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002584:Cervix Uteri / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D004717:Endometrium / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009928:Organ Specificity; D010755:Organophosphates / Q000494:pharmacology*; D061251:Primary Cell Culture; D011374:Progesterone / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D010755:Organophosphates; C583447:tenofovir diphosphate; D011374:Progesterone; D004958:Estradiol; D000225:Adenine