Depot Medroxyprogesterone Acetate Use Is Associated With Elevated Innate Immune Effector Molecules in Cervicovaginal Secretions of HIV-1–Uninfected Women

Abstract

OBJECTIVE The effects of sex hormones on the immune defenses of the female genital mucosa and its susceptibility to infections are poorly understood. The injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may increase risk of HIV-1 acquisition. We assessed the local concentration in the female genital mucosa of cationic polypeptides with reported antiviral activity in relation to DMPA use. METHODS HIV-1-uninfected women were recruited from among couples testing for HIV in Nairobi, Kenya. Cervicovaginal secretion (CVS) samples were collected and the concentrations of HNP1–3, LL-37, lactoferrin, HBD-2 and SLPI were measured by enzyme-linked immunosorbent assays.. Levels of cationic polypeptides in CVS were compared between women who were not using hormonal contraception and those using DMPA, oral, or implantable contraception. RESULTS Among 228 women, 165 (72%) reported not using hormonal contraception at enrollment, 41 (18%) used DMPA, 16 (7%) used an oral contraceptive, and 6 (3%) used a contraceptive implant. Compared to non-users of hormonal contraception, DMPA users had significantly higher mean levels of HNP1–3 (2.38 vs. 2.04 log10 ng/ml; p=0.024), LL-37 (0.81 vs. 0.40 log10 ng/ml; p=0.027), and lactoferrin (3.03 vs. 2.60 log10 ng/ml; p=0.002), whereas SLPI and HBD-2 were similar. CONCLUSIONS Although all analyzed cationic polypeptides have intrinsic antiviral capacity, their interaction and cumulative effect on female genital mucosa susceptibility to infections in vivo has yet to be unraveled. This study suggests a potential mechanism underlying the effect of DMPA on the innate immune defenses, providing a rationale to investigate its effect on HIV-1 acquisition risk.

Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility

“…Our findings indicating a general immune activation phenotype during the luteal phase may reflect a response similar to that induced by injectable contraceptives. For instance, a study examining DMPA use and a list of predefined innate immune factors found that alpha-defensins 1 to 3, LL-37 (cathelicidin), and lactoferrin were found at significantly higher levels in the secretions of DMPA users (56). Indeed, these findings match what was found in our study during the progesterone-dominant luteal phase.…”

Impact of etonogestrel implant use on T-cell and cytokine profiles in the female genital tract and blood

“…The results of our study highlight few changes in the lower genital tract inflammatory environment following Eng-Implant initiation. While several studies have evaluated genital tract immune changes after use of other hormonal contraceptive methods [17][18][19][20][21][22][23][48][49][50][51][52][53][54][55][56][57][58][59][60][61], to our knowledge, no published study has evaluated Eng-Implant. We report an increase in the proportion of CD4 T-cells expressing the co-receptor CCR5 at the genital mucosa with Eng-Implant use that could be associated with increased risk of HIV infection; however, not all our findings relate a clear picture of increased susceptibility.…”

The vaginal microbiome amplifies sex hormone‐associated cyclic changes in cervicovaginal inflammation and epithelial barrier disruption

“…37,38 Underlying molecular signatures for these observations resemble those of increased HIV susceptibility during inflammatory conditions, including increased levels of secreted chemokines/cytokines, proteases, and markers of epithelial barrier disruption. 7,32,39,40 An increase in cervicovaginal HIV/SIV target cells has been shown in humans 37,41 and non-human primates 42 in response to high levels of endogenous and exogenous progestin. In the present study, a distinct and specific proteomic signature of activated neutrophil-related immune pathways was observed in the LUT vs OV phase and to a lesser extent in the FOL phase.…”