The immunological basis of preterm birth in HIV-1 infected pregnant women

Abstract

Hypotheses HIV infection and combination antiretroviral therapy (cART) used to prevent mother-to-child-transmission of HIV in pregnancy increase the risk of preterm birth (PTB). We hypothesise that the use of cART, particularly protease inhibitor (PI) regimes, induce a pro-inflammatory environment at the fetal maternal unit, which triggers labour to occur at an earlier point in gestation than would occur without HIV-1 infection or cART. We also hypothesise that local cervicovaginal fluid (CVF) will be more informative regarding immune function than plasma. Specific aims -To understand the inflammatory mechanisms underlying PTB in HIV1infected and uninfected women -To elucidate if PI-based cART regimes are associated with greater concentrations of inflammatory cytokines compared to non-PI-based cART regimes in pregnancy -To characterise inflammatory and immune proteins in the CVF of HIV-1 infected pregnant women and compare by ART exposure and prematurity with a view to identifying potential PTB biomarkers. Results PTB in HIV-1 infected women was associated with greater circulating activated T cells and abundance of vaginal Gardnerella and Prevotella species. HIV-1 infected pregnant women have a high prevalence of L. iners and diverse anaerobic bacteria dominant vaginal community state types. Pre-conception cART was associated with greater abundance of Gardnerella vaginalis and a reduction in circulating activated T cells but not to the same level as observed in uninfected pregnant women. Length of time on cART was associated with an increase in plasma IL-12, the macrophage activating cytokine, indicating a pro-inflammatory 11 shift in cytokine environment. HIV-1 infected pregnant women had much higher inflammatory cytokines in their CVF. In HIV-1 infected pregnant women vaginal bacterial diversity was positively correlated with CVF pro-inflammatory cytokine IL-1E, known to be associated with PTB. Directed exploration of the CVF proteome in HIV-1 infected pregnant women revealed high abundance of immune proteins associated with macrophage and neutrophil activation, and Extracellular Matrix (ECM) modifiers such as matrix metalloproteinases (MMPs). These proteins were especially abundant in women receiving PI-based cART. Significance These data indicate that ART may modulate the local bacterial species; perhaps through selective pressure and that the vaginal bacterial communities observed in HIV-1 infected women are pro-inflammatory and associated with PTB. Local CVF inflammation and immune activation is exaggerated in these HIV-1 infected women and not fully reversed with cART. The presence of bacterial antigen in the context of enhanced local innate and adaptive inflammatory immune response is likely responsible for up-regulating downstream NFκB pathways such as induction of MMPs, known to be association with induction of labour. Contribution to academic area A greater understanding of the mechanisms behind this phenomenon enable us to greater define the toxicity of certain antiretroviral classes or specific drugs in pregnancy and assess newer drugs using the same techniques. Optimising the risk stratification in these women, perhaps through application of improved PTB biomarkers or regular vaginal bacterial screening, may enable improved targeted risk reduction strategies e.g. progesterone, antibiotics or probiotics.