Maraviroc, tenofovir disoproxil fumarate and dapivirine, activate progesterone receptor B in the absence of progestogens

Biochem Biophys Res Commun. 2020 Dec 17;533(4):1027-1033. doi: 10.1016/j.bbrc.2020.09.107. Epub 2020 Oct 2.


Antiretroviral therapy has slowed the HIV/AIDS pandemic and is currently being used as a prophylactic measure for individuals at high risk of infection. However, concerns over adverse effects of long-term use need to be explored. We hypothesize that this may occur, at least in part, through off-target effects via select steroid receptors (SRs) that broadly regulate multiple physiological processes. We investigated the effects of maraviroc (MVC), tenofovir disoproxil fumarate (TDF), and dapivirine (DPV) on progesterone receptor B (PR-B) transcriptional activity. We found that MVC and TDF activate PR-B transcription in the absence of progestogens on a PR-regulated promoter reporter construct and on endogenous PR-regulated genes. MVC and TDF exhibited no direct binding to PR-B; however, increased PR-B phosphorylation was detected with TDF but not MVC. DPV transactivated gilz and ptgs2 in the absence of progestogens and exhibited PR-B binding while showing no effects on phosphorylation, suggesting that it may activate PR-B through a direct mechanism. Our study shows that potential off-target immunomodulatory effects of MVC, TDF and DPV occur in vitro and these are most likely mediated by different mechanisms of PR-B activation.

Keywords: Antiretroviral drugs; Ligand-independent activation; Progesterone receptor; Progestins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-HIV Agents / adverse effects*
  • Anti-HIV Agents / pharmacokinetics
  • Binding, Competitive
  • Cell Line
  • Contraceptive Agents, Hormonal / pharmacokinetics
  • Contraceptive Agents, Hormonal / pharmacology
  • HIV Infections / drug therapy
  • HIV-1
  • Humans
  • Immunologic Factors / adverse effects
  • In Vitro Techniques
  • Levonorgestrel / pharmacokinetics
  • Levonorgestrel / pharmacology
  • Maraviroc / adverse effects*
  • Maraviroc / pharmacokinetics
  • Phosphorylation
  • Progesterone Congeners / pharmacokinetics
  • Progesterone Congeners / pharmacology
  • Pyrimidines / adverse effects*
  • Pyrimidines / pharmacokinetics
  • Receptors, Progesterone / agonists*
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Tenofovir / adverse effects*
  • Tenofovir / pharmacokinetics
  • Transcriptional Activation / drug effects


  • Anti-HIV Agents
  • Contraceptive Agents, Hormonal
  • Immunologic Factors
  • Progesterone Congeners
  • Pyrimidines
  • Receptors, Progesterone
  • progesterone receptor B
  • Levonorgestrel
  • Tenofovir
  • Maraviroc
  • Dapivirine