Background: Long acting injectable hormonal contraceptives, most commonly in the form of depot medroxyprogesterone acetate (DMPA), are inexpensive and easy to use, but may be linked to increased risk of HIV-1 acquisition. Cationic polypeptides are the principal effector molecules of the innate immune response in the vaginal mucosa, and higher levels of some polypeptides have been associated with increased risk of HIV infection. We hypothesize that DMPA modifies the innate immune response in the vaginal mucosal by increasing cationic polypeptides, contributing to the association between DMPA and HIV risk.
Methodology: We recruited HIV-1-exposed seronegative (HESN) women from HIV-discordant relationships and low-risk control women from concordant negative relationships in Nairobi, Kenya. Cervicovaginal lavage (CVL) samples were collected and enzyme-linked immunosorbent assays (ELISA) were used to measure cationic polypeptide concentrations. Cervicovaginal IgA was assessed for HIV-1-neutralizing activity by a peripheral blood mononuclear cellbased assay using an HIV-1 clade A primary isolate.
Results: Among 160 HESN women and 73 low-risk control women, 169 (73%) reported not using hormonal contraception at enrollment, 41 (18%) used DMPA, 16 (7%) used an oral contraceptive, and 7 (3%) used an implantable form of hormonal contraception. There were no differences between HESN and control women in their levels of human neutrophil peptides 1-3 (HNP1-3) (p=0.445) or LL-37 (p=0.512). Combining HESN and low-risk control women, compared to women not using hormonal contraception, DMPA users had significantly higher mean levels of HNP1-3 (2.38 vs. 2.05 log10 ng/ml; p=0.024) and LL-37 (0.84 vs. 0.48 log10 ng/ml; p=0.026). These associations did not differ between HESN and control women (p=0.639). DMPA use was not associated with levels of secretory leukocyte protease inhibitor (SLPI) (p=0.776).
Conclusions: We found that HNP1-3 and LL-37 cationic polypeptides were elevated in the CVL fluid of HIV-1 seronegative women using DMPA, regardless of HIV-1 exposure. While these polypeptides have intrinsic antiviral capacity, they are also potent recruiters of target cells for HIV infection. As a result, higher levels of HNP1-3 and LL-37 have been associated with increased HIV infection risk. A potential mechanism for the risk associated with injectable hormonal contraceptive use may be through upregulation of these polypeptides in the vaginal mucosa, resulting in recruitment of dendritic cells that are susceptible to HIV infection. This may provide independent evidence supporting a biological mechanism for increased HIV acquisition seen with DMPA.