Abstract
BackgroundHIV exposed seronegative (HESN) women represent the population most in need of a prophylactic antiviral strategy. Mucosal cationic polypeptides can potentially be regulated for this purpose and we here aimed to determine their endogenous expression and HIV neutralizing activity in genital secretions of women at risk of HIV infection.Methodology/Principal FindingsCervicovaginal secretions (CVS) of Kenyan women in HIV-serodiscordant relationships (HESN, n = 164; HIV seropositive, n = 60) and low-risk controls (n = 72) were assessed for the cationic polypeptides HNP1–3, LL-37 and SLPI by ELISA and for HIV neutralizing activity by a PBMC-based assay using an HIV primary isolate. Median levels of HNP1–3 and LL-37 in CVS were similar across study groups. Neither HSV-2 serostatus, nor presence of bacterial vaginosis, correlated with levels of HNP1–3 or LL-37 in the HESN women. However, an association with their partner's viral load was observed. High viral load (>10,000 HIV RNA copies/ml plasma) correlated with higher levels of HNP1–3 and LL-37 (p = 0.04 and 0.03, respectively). SLPI was most abundant in the low-risk group and did not correlate with male partner's viral load in the HESN women. HIV neutralizing activity was found in CVS of all study groups. In experimental studies, selective depletion of cationic polypeptides from CVS rendered the remaining CVS fraction non-neutralizing, whereas the cationic polypeptide fraction retained the activity. Furthermore, recombinant HNP1–3 and LL-37 could induce neutralizing activity when added to CVS lacking intrinsic activity.Conclusions/SignificanceThese findings show that CVS from HESN, low-risk, and HIV seropositive women contain HIV neutralizing activity. Although several innate immune proteins, including HNP1–3 and LL-37, contribute to this activity these molecules can also have inflammatory properties. This balance is influenced by hormonal and environmental factors and in the present HIV serodiscordant couple cohort study we show that a partner's viral load is associated with levels of such molecules.
Highlights
Mucosal surfaces of the female genital tract are portals for sexual transmission of microbes and viruses, and cationic antimicrobial polypeptides are the principal effector molecules of mucosal innate immunity
Demographic data and levels of antiviral cationic polypeptides in cervicovaginal secretions (CVS) samples In the present study, CVS samples were assessed from a total of 296 study participants: HIV seropositive (HIV pos, n = 60) and HIV seronegative (HESN, n = 164) women representing the serodiscordant couple cohort as well as HIV seronegative (Lowrisk, n = 72) women living with a seroconcordant HIV-negative male partner
Less secretory leukocyte protease inhibitor (SLPI) was present in the HIV positive group than in the other two groups (HIV pos vs HIV exposed seronegative (HESN): p = 0.013; HIV pos vs Low-risk: p,0.001); likewise, the HESN group contained less SLPI than the low-risk group (HESN vs Low-risk p = 0.005) (Figure 1)
Summary
Mucosal surfaces of the female genital tract are portals for sexual transmission of microbes and viruses, and cationic antimicrobial polypeptides are the principal effector molecules of mucosal innate immunity. Together with other innate immune cells and molecules, as well as physical and chemical barriers (mucus, low pH, epithelial integrity), these antimicrobials normally contribute to an efficient barrier against low dose HIV exposure during sexual intercourse with an HIV infected partner [1,2]. Antiviral cationic polypeptides are secreted from immune and epithelial cells into cervicovaginal secretions (CVS) and can potentially be regulated selectively by vaccines and microbicides against mucosal infections. Mucosal cationic polypeptides can potentially be regulated for this purpose and we here aimed to determine their endogenous expression and HIV neutralizing activity in genital secretions of women at risk of HIV infection
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