Sex hormones regulate tenofovir-diphosphate in female reproductive tract cells in culture

• Published in: PloS one 2014-06, Vol.9 (6), p.e100863-e100863
• Main Authors: Shen, Zheng, Fahey, John V, Bodwell, Jack E, Rodriguez-Garcia, Marta, Kashuba, Angela D M, Wira, Charles R
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Acquired immune deficiency syndrome; Adenine - analogs & derivatives; Adenine - pharmacology; Adult; Aged; AIDS; Analysis; Anti-HIV Agents - pharmacology; Antiretroviral drugs; Biological Transport - drug effects; Biology and Life Sciences; Blood; CD14 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cell culture; Cervix Uteri - cytology; Cervix Uteri - metabolism; Cervix Uteri - surgery; Disease prevention; Drug therapy; Endometrium; Endometrium - cytology; Endometrium - metabolism; Endometrium - surgery; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Estradiol - pharmacology; Female; Females; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Health aspects; HIV; HIV infections; Hormones; Human immunodeficiency virus; Humans; Incubation; Infection; Infections; Intracellular; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Medicine; Medicine and Health Sciences; Menstruation; Middle Aged; Monocytes; Neurobiology; Neurosciences; Organ Specificity; Organophosphates - pharmacology; Pandemics; Pathogens; Peripheral blood; Physiology; Primary Cell Culture; Progesterone; Progesterone - pharmacology; Prophylaxis; Reproductive system; Sex; Sex hormones; Sexually transmitted diseases; STD; Studies; T cells; Tenofovir; Tissues
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100863

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.