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The contraceptive medroxyprogesterone acetate, unlike norethisterone, directly increases R5 HIV-1 infection in human cervical explant tissue at physiologically relevant concentrations

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dc.contributor.authorRay, R.M.
dc.contributor.authorMaritz, M.F.
dc.contributor.authorAvenant, C.
dc.contributor.authorTomasicchio, M.
dc.contributor.authorDlamini, S.
dc.contributor.authorvan der Spuy, Z.
dc.contributor.authorHapgood, J.P.
dc.date.issued2019
dc.descriptionData source: Supplementary information, https://doi.org/10.1038/s41598-019-40756-7
dc.description.abstractThe intramuscular progestin-only injectable contraceptive, depo-medroxyprogesterone acetate (DMPA-IM), is more widely used in Sub-Saharan Africa than another injectable contraceptive, norethisterone enanthate (NET-EN). Epidemiological data show a significant 1.4-fold increased risk of HIV-1 acquisition for DMPA-IM usage, while no such association is shown from limited data for NET-EN. We show that MPA, unlike NET, significantly increases R5-tropic but not X4-tropic HIV-1 replication ex vivo in human endocervical and ectocervical explant tissue from pre-menopausal donors, at physiologically relevant doses. Results support a mechanism whereby MPA, unlike NET, acts via the glucocorticoid receptor (GR) to increase HIV-1 replication in cervical tissue by increasing the relative frequency of CD4+ T cells and activated monocytes. We show that MPA, unlike NET, increases mRNA expression of the CD4 HIV-1 receptor and CCR5 but not CXCR4 chemokine receptors, via the GR. However, increased density of CD4 on CD3+ cells was not observed with MPA by flow cytometry of digested tissue. Results suggest that DMPA-IM may increase HIV-1 acquisition in vivo at least in part via direct effects on cervical tissue to increase founder R5-tropic HIV-1 replication. Our findings support differential biological mechanisms and disaggregation of DMPA-IM and NET-EN regarding HIV-1 acquisition risk category for use in high risk areas.
dc.identifier.citationScientific Reports, 2019; 9(1, article no. 4334)
dc.identifier.doi10.1038/s41598-019-40756-7
dc.identifier.issn2045-2322
dc.identifier.issn2045-2322
dc.identifier.urihttps://hdl.handle.net/11541.2/138668
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.fundingEunice Kennedy Shriver National Institute of Child Health and Human Development R01HD083026
dc.rightsCopyright 2019 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. (http://creativecommons.org/licenses/by/4.0/)
dc.source.urihttps://doi.org/10.1038/s41598-019-40756-7
dc.subjectcontraceptive
dc.subjectDMPA-IM
dc.subjectinfection
dc.subjectcervical tissue
dc.titleThe contraceptive medroxyprogesterone acetate, unlike norethisterone, directly increases R5 HIV-1 infection in human cervical explant tissue at physiologically relevant concentrations
dc.typeJournal article
pubs.publication-statusPublished
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