Cervicovaginal levels of lactoferrin, secretory leukocyte protease inhibitor, and RANTES and the effects of coexisting vaginoses in human immunodeficiency virus (HIV)-seronegative women with a high risk of heterosexual acquisition of HIV infection.

Innate immune factors in mucosal secretions may influence human immunodeficiency virus type 1 (HIV-1) transmission. This study examined the levels of three such factors, genital tract lactoferrin [Lf], secretory leukocyte protease inhibitor [SLPI], and RANTES, in women at risk for acquiring HIV infection, as well as cofactors that may be associated with their presence. Women at high risk for HIV infection meeting established criteria (n = 62) and low-risk controls (n = 33) underwent cervicovaginal lavage (CVL), and the CVL fluid samples were assayed for Lf and SLPI. Subsets of 26 and 10 samples, respectively, were assayed for RANTES. Coexisting sexually transmitted infections and vaginoses were also assessed, and detailed behavioral information was collected. Lf levels were higher in high-risk (mean, 204 ng/ml) versus low-risk (mean, 160 ng/ml, P = 0.007) women, but SLPI levels did not differ, and RANTES levels were higher in only the highest-risk subset. Lf was positively associated only with the presence of leukocytes in the CVL fluid (P < 0.0001). SLPI levels were lower in women with bacterial vaginosis [BV] than in those without BV (P = 0.04). Treatment of BV reduced RANTES levels (P = 0.05). The influence, if any, of these three cofactors on HIV transmission in women cannot be determined from this study. The higher Lf concentrations observed in high-risk women were strongly associated with the presence of leukocytes, suggesting a leukocyte source and consistent with greater genital tract inflammation in the high-risk group. Reduced SLPI levels during BV infection are consistent with an increased risk of HIV infection, which has been associated with BV. However, the increased RANTES levels in a higher-risk subset of high-risk women were reduced after BV treatment.

Human cervicovaginal lavage fluid contains an inhibitor of HIV binding to dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin.

A small percentage of women at high risk for human immunodeficiency virus (HIV) exposure remain uninfected for long periods, protected by unknown mechanisms. We hypothesized that one mechanism could be inhibition of interactions between HIV and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) in the genital tract. In an analysis of 95 cervicovaginal lavage samples, we found that 12 (12.6%) strongly inhibited the binding of laboratory-adapted and primary HIV-1 isolates to B-THP-1/DC-SIGN cells in a dose-dependent manner, independently of the donor's risk of exposure. Three of 5 primary isolates were also blocked from binding to primary DCs. The inhibitor has a high molecular weight, is heat stable, and is resistant to trypsin. It is sensitive to pronase and periodate, indicating that it is likely a glycoprotein. Mannosidase digestion and concanavalin A adsorption indicate that the terminal residues of the carbohydrate are not mannose. Mechanistic experiments indicate that the inhibitor acts via binding to DC-SIGN. Further study of such inhibitors may help to elucidate the role played by DC-SIGN in HIV transmission.