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
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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.