Medroxyprogesterone acetate alters the vaginal microbiota and microenvironment in women and increases susceptibility to HIV-1 in humanized mice

Wessels, Jocelyn M.; Lajoie, Julie; Cooper, Maeve I. J. Hay; Omollo, Kenneth; Felker, Allison M.; Vitali, Danielle; Dupont, H; Nguyen, Philip V.; Mueller, Kristen; Vahedi, Fatemeh; Kimani, Joshua; Oyugi, Julius; Cheruiyot, Juliana; Mungai, Joseph Maina; Deshière, Alexandre; Tremblay, Michel J.; Mazzulli, Tony; Stearns, Jennifer C.; Ashkar, Ali A.; Fowke, Keith R.; Surette, Michael G.; Kaushic, Charu

doi:10.1242/dmm.039669

Cited by 30 publications

(47 citation statements)

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“…The NRF-2 is a pathway of defense against oxidative stress; downstream effects lead to increased glucose metabolism [ 49 ], and this pathway can be influenced by progestins [ 50 ]. Indeed, DMPA has been associated with altered glucose metabolism [ 51 ] and type-2 diabetes [ 52 ]. Glucose metabolism has previously been shown to be important for the recruitment and activation of CD4 + T cells [ 53 ], and studies have suggested that glycolysis is an important pathway in the CD4+ T cell immune response [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

“…In most cases, use of progestin-based hormonal contraception has been associated with a reduction in incidence of BV [ 32 , 58 , 59 ], and higher levels of vaginal Lactobacillus spp. [ 29 ]; however, others have reported a decrease the levels of vaginal H 2 O 2 -producing lactobacilli [ 43 , 60 , 61 ], increases in microbial diversity [ 51 ], or no effect on microbiome composition [ 62 ]. We observed only minor differences in microbiome composition and no changes to microbiome-derived functional pathways.…”

Section: Discussionmentioning

confidence: 99%

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Vaginal microbiome-hormonal contraceptive interactions associate with the mucosal proteome and HIV acquisition

et al. 2020

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Alterations to the mucosal environment of the female genital tract, such as genital inflammation, have been associated with increased HIV acquisition in women. As the microbiome and hormonal contraceptives can affect vaginal mucosal immunity, we hypothesized these components may interact in the context of HIV susceptibility. Using previously published microbiome data from 685 women in the CAPRISA-004 trial, we compared relative risk of HIV acquisition in this cohort who were using injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In women who were Lactobacillus-dominant, HIV acquisition was 3-fold higher in women using DMPA relative to women using NET-EN or COC (OR: 3.27; 95% CI: 1.24–11.24, P = 0.0305). This was not observed in non-Lactobacillus-dominant women (OR: 0.95, 95% CI: 0.44–2.15, P = 0.895) (interaction P = 0.0686). Higher serum MPA levels associated with increased molecular pathways of inflammation in the vaginal mucosal fluid of Lactobacillus-dominant women, but no differences were seen in non-Lactobacillus dominant women. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Vaginal microbiome-hormonal contraceptive interactions associate with the mucosal proteome and HIV acquisition

et al. 2020

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“…The metaanalysis of observational data for DMPA-IM relative to no contraception or mainly condom use are currently the best estimate of the HIV risks associated with DMPA-IM and are mostly consistent with a large body of other clinical, animal, and laboratory studies indicating several plausible biological mechanisms whereby DMPA-IM may increase HIV acquisition relative to no contraception. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52]72 The ECHO trial results on relative HIV risks between the three methods are subject to several limitations and uncertainties. They provide evidence that the LNG implant may be associated with lower HIV risk than DMPA-IM and the copper-IUD.…”

Section: What Do the Echo Results Tell Us About The Risks Of Hiv Acqumentioning

confidence: 99%

Is the Injectable Contraceptive Depo-Medroxyprogesterone Acetate (DMPA-IM) Associated with an Increased Risk for HIV Acquisition? The Jury Is Still Out

Hapgood

2020

AIDS Research and Human Retroviruses

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Intramuscular depo-medroxyprogesterone acetate (DMPA-IM) is the most widely used hormonal contraceptive in sub-Saharan Africa. Previous meta-analyses of observational studies found a significant 40%-50% increased risk associated with DMPA-IM use, relative to no contraception or infrequent condom use. This raised substantial concerns, although these studies had important limitations. Consequently, the open-label randomized Evidence for Contraceptive Options and HIV Outcomes trial was conducted, designed primarily to detect a 50% or greater difference in HIV risk between DMPA-IM, the levonorgestrel (LNG) implant, and the copper-intrauterine device. The ECHO study, published in July 2019, concluded that there is no substantial difference in HIV risk among the methods evaluated, and that all three methods are safe and highly effective. In response, the WHO relaxed the Medical Eligibility Criteria for DMPA-IM use among women at high HIV risk in August 2019. However, two of the three comparisons in the ECHO trial could rule out neither a 50% increase nor no change in HIV risk for one contraceptive compared with another. The study had limitations and the results contained considerable uncertainty. They also did not inform on associated HIV risk for any one of the individual methods due to the absence of a control group such as no contraception or only infrequent condom use. The HIV risks associated with LNG implant and copper-IUD relative to no contraception or infrequent condom use are unknown and these cannot be seen as controls, nor did the authors claim them to be. The results will be discussed in the context of their limitations, what they add to the body of work to date on contraception and HIV acquisition, and the implications of the findings and reports thereof for future research and contraceptive choice.

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“…Briefly, these mechanisms include modification of the protective epithelial barrier lining the female genital tract, altered genital immunity and defense (cytokines, chemokines, defensins, antibodies, etc. ), a change in HIV-1 target cell activation or frequency (T cells, dendritic cells (DCs), and macrophages), and most recently modification of the vaginal microbiota 13 , 14 . We recently characterized and described an intravaginal infection model of HIV-1 in humanized mice 15 (Hu-mice) where we demonstrated that frequency of human CD45+ target cells was the primary determinant of HIV-1 infection following intravaginal inoculation, and that viral dose was a determinant of viral dissemination and plasma titres during early infection 15 .…”

Section: Introductionmentioning

confidence: 99%

Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice

Wessels

Nguyen

Vitali

et al. 2021

Sci Rep

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The progestin-based hormonal contraceptive Depot Medroxyprogesterone Acetate (DMPA) is widely used in sub-Saharan Africa, where HIV-1 is endemic. Meta-analyses have shown that women using DMPA are 40% more likely than women not using hormonal contraceptives to acquire Human Immunodeficiency Virus (HIV-1). Therefore understanding how DMPA increases susceptibility to HIV-1 is an important public health issue. Using C57BL/6 mice and our previously optimized humanized mouse model (NOD-Rag1tm1Mom Il2rgtm1Wjl transplanted with hCD34-enriched hematopoietic stem cells; Hu-mice) where peripheral blood and tissues are reconstituted by human immune cells, we assessed how DMPA affected mucosal barrier function, HIV-1 susceptibility, viral titres, and target cells compared to mice in the diestrus phase of the estrous cycle, when endogenous progesterone is highest. We found that DMPA enhanced FITC-dextran dye leakage from the vaginal tract into the systemic circulation, enhanced target cells (hCD68+ macrophages, hCD4+ T cells) in the vaginal tract and peripheral blood (hCD45+hCD3+hCD4+hCCR5+ T cells), increased the rate of intravaginal HIV-1 infection, extended the window of vulnerability, and lowered vaginal viral titres following infection. These findings suggest DMPA may enhance susceptibility to HIV-1 in Hu-mice by impairing the vaginal epithelial barrier, increasing vaginal target cells (including macrophages), and extending the period of time during which Hu-mice are susceptible to infection; mechanisms that might also affect HIV-1 susceptibility in women.

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Medroxyprogesterone acetate alters the vaginal microbiota and microenvironment in women and increases susceptibility to HIV-1 in humanized mice

Cited by 30 publications

References 61 publications

Vaginal microbiome-hormonal contraceptive interactions associate with the mucosal proteome and HIV acquisition

Vaginal microbiome-hormonal contraceptive interactions associate with the mucosal proteome and HIV acquisition

Is the Injectable Contraceptive Depo-Medroxyprogesterone Acetate (DMPA-IM) Associated with an Increased Risk for HIV Acquisition? The Jury Is Still Out

Depot medroxyprogesterone acetate (DMPA) enhances susceptibility and increases the window of vulnerability to HIV-1 in humanized mice

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