Medroxyprogesterone acetate, unlike norethisterone, increases HIV-1 replication  in human peripheral blood mononuclear cells and an indicator cell line, via  mechanisms involving the glucocorticoid receptor, increased CD4/CD8 ratios and  CCR5 levels

Maritz MF, Ray RM, Bick AJ, Tomasicchio M, Woodland JG, Govender Y, Avenant C, Hapgood JP

doi:10.1371/journal.pone.0196043

PloS One, 13(4), e0196043, 2018

Medroxyprogesterone acetate, unlike norethisterone, increases HIV-1 replication in human peripheral blood mononuclear cells and an indicator cell line, via mechanisms involving the glucocorticoid receptor, increased CD4/CD8 ratios and CCR5 levels

Michelle F Maritz , Roslyn M Ray , Alexis J Bick

Author affiliations

University of Cape Town ROR

DOI10.1371/journal.pone.0196043 PMID29698514

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Abstract

High usage of progestin-only injectable contraceptives, which include the intramuscular injectables depo-medroxyprogesterone acetate (DMPA-IM, Depo-Provera) and norethisterone (NET) enanthate (NET-EN or Nur-Isterate), correlates worldwide with areas of high HIV-1 prevalence. Epidemiological data show a significant association between usage of DMPA-IM and increased HIV-1 acquisition but no such association from limited data for NET-EN. Whether MPA and NET have similar effects on HIV-1 acquisition and pathogenesis, and the relationship between these effects and the dose of MPA, are critical issues for women's health and access to suitable and safe contraceptives. We show for the first time that MPA, unlike NET, significantly increases HIV-1 replication in peripheral blood mononuclear cells (PBMCs) and a cervical cell line model. The results provide novel evidence for a biological mechanism whereby MPA, acting via the glucocorticoid receptor (GR), increases HIV-1 replication by at least in part increasing expression of the CCR5 HIV-1 coreceptor on target T-lymphocytes. MPA, unlike NET, also increases activation of T-cells and increases the CD4/CD8 ratio, suggesting that multiple mechanisms are involved in the MPA response. Our data offer strong support for different biological mechanisms for MPA versus NET, due to their differential GR activity. The dose-dependence of the MPA response suggests that significant effects are observed within the range of peak serum levels of progestins in DMPA-IM but not NET-EN users. Dose-response results further suggest that effects of contraceptives containing MPA on HIV-1 acquisition and disease progression may be critically dependent on dose, time after injection and intrinsic factors that affect serum concentrations in women.

Topics

Contraception/Comparison > Injectable Progestins > HIV-1 Replication Risk Reproductive Endocrinology > Progestin Pharmacology > Glucocorticoid Receptor Effects Research Methodology > In Vitro Study > Contraceptive Immunologic Effects

Maritz Ray medroxyprogesterone acetate norethisterone HIV-1 replication PBMC comparison, DMPA Depo-Provera injectable contraceptive HIV replication in vitro peripheral blood, MPA increases HIV-1 p24 antigen GR glucocorticoid receptor mediated immunosuppression, norethisterone enanthate NET-EN no HIV replication increase progestin comparison, injectable contraceptive HIV risk Sub-Saharan Africa women progestin differential effect, PLoS One 2018 medroxyprogesterone HIV PBMC replication progestin type matters, glucocorticoid receptor activation MPA T-cell immunosuppression HIV vulnerability, progestin-only contraceptive HIV acquisition risk DMPA versus NET-EN safety, intramuscular injectable contraceptive HIV-1 p24 viral load in vitro comparison, Depo-Provera HIV susceptibility immunologic mechanism women Sub-Saharan Africa

PMID 29698514 29698514 DOI 10.1371/journal.pone.0196043 10.1371/journal.pone.0196043

Cite this article

Maritz, M. F., Ray, R. M., Bick, A. J., Tomasicchio, M., Woodland, J. G., Govender, Y., Avenant, C., & Hapgood, J. P. (2018). Medroxyprogesterone acetate, unlike norethisterone, increases HIV-1 replication in human peripheral blood mononuclear cells and an indicator cell line, via mechanisms involving the glucocorticoid receptor, increased CD4/CD8 ratios and CCR5 levels. PloS one, 13(4), e0196043. https://doi.org/10.1371/journal.pone.0196043

Keywords

CCR5 Protein, Human, CD4 Antigens, RNA, Small Interfering, Receptors, CCR5, Receptors, Glucocorticoid, Mifepristone, Medroxyprogesterone Acetate, Norethindrone

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