Characterizing immune activation in HIV-exposed but uninfected infants in the first year of life

HIV-exposed uninfected (HEU) infants experience multiple health complications compared to HIV-unexposed (HUU) infants, including immune dysregulation in the first year of life. In utero exposure to maternal inflammation associated with HIV infection is a proposed mechanism of HEU immune dysregulation. This study compared markers of inflammation and immune activation over the first year of life between HEU and HUU infants.

Stored plasma samples were sourced from HEU infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) protocol P1025, a prospective observational study that enrolled US pregnant people with HIV and their infants between 2002-2013, and from 3 studies that enrolled healthy HUU infants in Aurora, CO. We used the MesoScale Discovery platform to measure 16 inflammatory and regulatory biomarkers at weeks 2, 6, 24 and 48 of life.

In a multivariable regression analysis of 135 HEU and 51 HUU infants adjusted for sex, race/ethnicity, delivery mechanism, gestational age and birth weight, we identified higher concentrations of several biomarkers in HUU compared to HEU infants, including: IL-17A, IL-1β, IL-4, TNFα, IL-5, IL-8, MCP1, CCL22, CCL3, and CCL4. Among HEU infants, maternal CD4+ T-lymphocyte count of <200 or 200-500 copies/mL at delivery was associated with higher infant concentrations of IFNγ, IL-6, CXCL10, TNFα, CCL3, and CCL4 and maternal viral load ≥400 RNA copies/ml at delivery was associated with higher infant IL-2 and IL-10.

We identified that HUU infants had higher concentrations of most immune biomarkers compared to HEU infants, in contrast to prior literature. We also observed that lower maternal CD4+ T-lymphocyte count and higher HIV viral load at delivery were associated with higher concentrations of several inflammatory biomarkers in HEU infants. This suggests that more advanced maternal HIV may be associated with heightened immune activation in HEU infants that persists into late infancy. These data suggest that there may be multiple subtypes of immune alterations in HEU infants, potentially existing on a spectrum spanning from immune activation to a regulatory or suppressed phenotype. Further studies are needed to determine the mechanisms through which in utero exposure to maternal HIV infection impacts infant immune development.