Abstract
BackgroundIn low and middle income countries, human immunodeficiency virus (HIV) exposed, uninfected (HEU) infants demonstrate higher morbidity and mortality than their unexposed counterparts. To determine possible immune correlates of this effect, we investigated the impact of in utero HIV exposure on the uninfected neonatal immune milieu and maternal factors mediating these abnormalities in a cohort of vaginally delivered mother-infants. Samples of delivery and cord blood plasma were selected from 22 Kenyan HIV-infected women and their HIV exposed uninfected (HEU) infants drawn from the pre-ARV era, while 19 Kenyan HIV-uninfected (HU) women and their infants were selected from a control cohort.ResultsCompared to HU cord plasma, HEU cord plasma contained significantly higher levels of pro-inflammatory cytokines interleukins (IL)-6 and -8 (both p < 0.001) and significantly lower levels of CXC motif chemokine 11 (CXC11) (p < 0.001). Mediation analysis demonstrated that maternal HIV infection status was a significant determinant of infant IL-8 responses: HEU status was associated with a ninefold higher infant:mother (cord:delivery) plasma levels of IL-8 (p < 0.005), whereas maternal viral load was negatively associated with HEU IL-8 levels (p = 0.04) and not associated with HEU IL-6 levels.ConclusionsExposure to maternal HIV infection drives an increase in prenatal IL-8 that is partially mediated by maternal cytokine levels. Differences between maternal and infant cytokine levels strongly suggest independent modulation in utero, consistent with prenatal immune activation. Elevated pro-inflammatory signals at birth may interfere with T cell responses at birth and subsequently influence immune maturation and the risk of morbidity and mortality in HEU infants.
Highlights
In low and middle income countries, human immunodeficiency virus (HIV) exposed, uninfected (HEU) infants demonstrate higher morbidity and mortality than their unexposed counterparts
Infants born to HIV infected and HIV uninfected groups of women were of similar birth-weight: 3.3 kg (IQR, 3.0– 3.6) vs 3.1 kg (IQR 2.9–3.5), respectively
Our study provides a direct link between maternal HIV infection and elevated levels of prenatal IL-6 and IL-8 measured in cord blood from infants who were born HIV uninfected and who did not acquire HIV through vaginal delivery and breastfeeding during the first year of life and who were unexposed to ARV
Summary
In low and middle income countries, human immunodeficiency virus (HIV) exposed, uninfected (HEU) infants demonstrate higher morbidity and mortality than their unexposed counterparts. It is evident that this has created a large and expanding number of HIV exposed but uninfected (HEU) infants. These infants experience increased rates of morbidity and mortality compared with their HIV unexposed (HU) counterparts. At birth cord blood T cells from HEU children can mount HIV-1 specific responses, indicating exposure to circulating maternal HIV antigen [6, 7]. There is controversy in the field as to the cause of the observed immune changes in HEU infants, the relative contribution of maternal health, and relative differences observed in HIV unexposed infants from the same communities. Plausible is that exposure to antiretroviral medications, poor nutrition, or exposure to multiple environmental antigens other than HIV, could stimulate a similar profile in HIV unexposed infants living in similar conditions
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