Abstract
The association between the use of the injectable contraceptive depot medroxyprogesterone acetate and HIV-1 susceptibility has been addressed mainly in respect to the changes occurring in the female genital mucosa and blood. However, one of the main sites of HIV-1 pathogenesis is lymphoid organs. To investigate the immunoregulatory effect of medroxyprogesterone acetate (MPA) at this site, human tonsillar tissue explants were infected ex vivo with either a CCR5 (BaL) or CXCR4 (LAI) HIV-1 variant and the release of p24gag and cytokines was measured in culture supernatant. The response to MPA was compared with that elicited by treatment with progesterone (P4) and dexamethasone (DEX), which selectively binds the glucocorticoid receptor, in donor-matched explant cultures. MPA treatment reduced the replication of both tested HIV-1 strains as well as the production of the mediators of inflammation IL-1β, IL-17A and CCL5, but not CCL20, in a similar way to DEX, whereas P4 had no effect on HIV-1 replication. The magnitude of both MPA and DEX-mediated responses was proportional to the length of exposure and/or administered dose. Blockage of the progesterone and glucocorticoid receptors with mifepristone abolished all observed changes in HIV-1 and cytokine production, and was associated with increased IL-22 levels in HIV-infected explants. Our data indicate that elevated doses of MPA may affect the immune responses in lymphoid tissue in a glucocorticoid-like fashion with an immediate impact on local HIV-1 replication.
Highlights
In spite of their higher efficacy compared to traditional barrier methods, Hormonal contraceptives (HC) do not protect against sexually transmitted infections (STIs)
We investigated the effect of medroxyprogesterone acetate (MPA) on human tonsillar lymphoid tissue explants infected ex vivo with human immunodeficiency virus (HIV)-1, in comparison with the anti-inflammatory drug and selective glucocorticoid receptor (GR) agonist dexamethasone (DEX) as well as P4
Our results suggest that MPA, at doses that are compatible with peak concentrations observed in serum of DMPA users, exerts an immunoregulatory effect on lymphoid tissue comparable to that elicited by DEX, with implications that may extend to local immunity at mucosal sites of virus transmission
Summary
The number of injectable HC users increased more than four times in the past 25 years due to the advantages offered by inexpensive, short-acting contraceptives that are as effective as other methods with fewer administrations. For this reason, injectables represent the method of choice in resource-limited settings including. Sub-Saharan Africa, where, with a prevalence of about 10%, injectables are the dominant contraceptive among women of reproductive age In spite of their higher efficacy compared to traditional barrier methods, HC do not protect against sexually transmitted infections (STIs). The ECHO study, a randomized trial conducted in
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