Reciprocal Modulation of Antiretroviral Drug and Steroid Receptor Function In Vitro
| Autor: | John G Woodland, Kim Enfield, Chanel Avenant, Salndave B. Skosana, Sigcinile Dlamini, Janet P. Hapgood, Alexis J. Bick, Zephne M van der Spuy, Michelle F. Maritz, Michael Kuipa, Johnson Mosoko Moliki |
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| Přispěvatelé: | Dlamini, S, Kuipa, M, Enfield, K, Skosana, S, Woodland, JG, Moliki, JM, Bick, AJ, van der Spuy, Z, Maritz, MF, Avenant, C, Hapgood, JP |
| Rok vydání: | 2019 |
| Předmět: |
Receptors
Steroid Cell Survival dapivirine Cell Pharmacology Antiviral Agents 03 medical and health sciences Receptors Glucocorticoid 0302 clinical medicine Glucocorticoid receptor In vivo Cell Line Tumor Progesterone receptor medicine Humans Pharmacology (medical) 030212 general & internal medicine Viability assay Tenofovir Receptor cell viability 030304 developmental biology Inflammation 0303 health sciences Chemistry Pyrimidines Infectious Diseases medicine.anatomical_structure Anti-Retroviral Agents inflammation Cell culture Peripheral Blood Stem Cells gene expression HIV-1 ARV Progestins Receptors Progesterone Glucocorticoid Transcription Factors medicine.drug |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.01890-19 |
| Popis: | Millions of women are exposed simultaneously to antiretroviral drugs (ARVs) and progestin-based hormonal contraceptives. Yet the reciprocal modulation by ARVs and progestins of their intracellular functions is relatively unexplored. We investigated the effects of tenofovir disoproxil fumarate (TDF) and dapivirine (DPV), alone and in the presence of select steroids and progestins, on cell viability, steroid-regulated immunomodulatory gene expression, activation of steroid receptors, and anti-HIV-1 activity in vitro. Both TDF and DPV modulated the transcriptional efficacy of a glucocorticoid agonist via the glucocorticoid receptor (GR) in the U2OS cell line. In TZM-bl cells, DPV induced the expression of the proinflammatory interleukin 8 (IL-8) gene while TDF significantly increased medroxyprogesterone acetate (MPA)induced expression of the anti-inflammatory glucocorticoid-induced leucine zipper (GILZ) gene. However, peripheral blood mononuclear cell (PBMC) and ectocervical explant tissue viability and gene expression results, along with TZM-bl HIV-1 infection data, are reassuring and suggest that TDF and DPV, in combination with dexamethasone (DEX) or MPA, do not reciprocally modulate key biological effects in primary cells and tissue. We show for the first time that TDF induces progestogen-independent activation of the progesterone receptor (PR) in a cell line. The ability of TDF and DPV to influence GR and PR activity suggests that their use may be associated with steroid receptor-mediated off-target effects. This, together with cell line and individual donor gene expression responses in the primary models, raises concerns that reciprocal modulation may cause side effects in a cell- and donor-specific manner in vivo. usc Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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