Cervical and systemic innate immunity predictors of HIV risk linked to genital herpes acquisition and time from HSV-2 seroconversion

Abstract

AbstractObjectivesTo examine innate immunity predictors of HIV-1 acquisition as biomarkers of HSV-2 risk and biological basis for epidemiologically established HIV-1 predisposition in HSV-2 infected women.MethodsWe analyzed longitudinal samples from HIV-1 negative visits of 1019 women before and after HSV-2 acquisition. We measured cervical and serum biomarkers of inflammation and immune activation previously linked to HIV-1 risk. Protein levels were Box–Cox transformed and odds ratios for HSV-2 acquisition were calculated based on top quartile or below/above median levels for all HSV-2 negative visits. Bivariate analysis determined the likelihood of HSV-2 acquisition by biomarker levels preceding infection. Linear mixed-effects models evaluated if biomarkers differed by HSV-2 status defined as negative, incident, or established infections with an established infection cut-off starting at 6 months.ResultsIn the cervical compartment, two biomarkers of HIV-1 risk (low SLPI and high BD-2) also predicted HSV-2 acquisition. In addition, HSV-2 acquisition was associated with IL-1β, IL-6, IL-8, MIP-3α, ICAM-1 and VEGF when below median levels. Systemic immunity predictors of HSV-2 acquisition were high sCD14 and IL-6, with highest odds when concomitantly increased (OR=2.23, 1.49-3.35). Concomitant systemic and mucosal predictors of HSV-2 acquisition risk included: 1) serum top quartile sCD14 with cervical low SLPI, VEGF and ICAM-1, or high BD-2; serum high IL-6 with cervical low VEGF and ICAM-1, SLPI, IL-1β and IL-6, and 3) serum low CRP with cervical high BD-2. Most cervical biomarkers were decreased after HSV-2 acquisition compared to the HSV-2 negative visits, with incident infections associated with a larger number of suppressed cervical biomarkers and lower serum IL-6 levels compared to established infections.ConclusionsA combination of systemic immunoinflammatory and cervical immunosuppressed states predicts HSV-2 acquisition. A persistently suppressed innate immunity during incident infection may add to the increased HIV-1 susceptibility.Key MessagesA combination of altered systemic and cervical immunity precedes and predicts risk of HSV-2 acquisition.Factors causing cervical mucosal imbalance (low SLPI and high BD-2) may predispose to both HIV-1 and HSV-2 acquisitionIn comparison to non-infected, HSV-2 infected women show suppressed cervical innate immunityCompared to women with established HSV-2 infection, those with incident infections within 6 months from seroconversion are more immunosuppressed both at the mucosal and peripheral level, adding to the biology of HIV predisposition.