The Contraceptive MPA, Unlike NET, Modulates Expression of Immune Function Genes and Increases HIV-1 Infection in Cervical Tissue Explants and PBMCs

Abstract

Background: The synthetic progestins medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET-EN) are widely used in developing countries as injectable contraceptives where disease burden is high. Some studies suggest that MPA unlike NET increases HIV-1 acquisition in women. Whether MPA and NET differentially affect HIV-1 infection and the expression of key genes relevant to HIV-1 acquisition via differential molecular mechanisms is key to understanding choice of progestin contraceptive for HIV-1 prevention. Methods: Regulation of selected genes was investigated in cervical tissue explants and peripheral blood mononuclear cells (PBMCs) by qRT-PCR western blotting and Luminex assays in response to physiologically relevant doses of progestogens. Infection assays were performed in the absence and presence of HIV-1 using HIV-1BAL-RENILLA or HIVpNL4.3 IMCs. The GR specific antagonist RU486 or GR siRNA knockdown were used to determine the role of the GR in modulating ligand-specific effects. Results: In PBMCs MPA like dexamethasone (DEX a GR specific agonist) showed anti-inflammatory effects decreasing pro-inflammatory IL6 IL8 and RANTES levels and increasing anti-inflammatory GILZ gene expression levels while NET and progesterone (P4) did not. In primary cervical tissue explants DEX and MPA repressed IL6 and IL8 and increased GILZ gene expression levels. Differential gene expression by MPA versus NET and P4 were mediated via the GR in PBMCs. Similarly MPA and DEX unlike NET and P4 increased HIV-1 replication in viable PBMCs. In primary cervical explants MPA but not NET increased HIV-1 replication. Conclusions: Collectively the data suggest that NET unlike MPA would be a safer choice of injectable progestin contraceptive in young women in high risk areas for HIV-1 infection. The molecular basis for this choice most likely involves differential effects of MPA as compared to NET and P4 on transcription of immunomodulatory genes due to their differential actions via the ubiquitous GR.