The effects of in utero HIV and ART exposure on infant T-cell and monocyte activation, function and regulation of immune-modulatory pathways

Abstract

Infection with HIV is associated with persistent immune dysfunction and activation. The study assessed whether maternal HIV status and cytokine/chemokine profiles impact infant growth, T-cell and monocyte activation, regulation, and monocyte responsiveness to stimulation at birth and early infancy. A total of 148 pregnant women – 71 pregnant women/mothers living with HIV (MLWH) and 77 without HIV – were recruited at 22 weeks’ gestation and followed until 12 months postpartum. Bloods were drawn from mothers at 28 weeks’ gestation and birth, and from infants at birth, six-, 10 and 14 weeks, and six months. All infants were HIV-negative. Compared to HIV-unexposed-uninfected infants, HIV-exposed-but-uninfected (HEU) infants had suboptimal growth from birth up to 12 months of age. MLWH had a lower CD4:CD8 ratio, increased mature CD4+ effector memory (EM) T-cells and a maturation arrest in CD8+ T-cells. MLWH also had increased T-cell activation, with higher programmed death protein-1 (PD-1) expression, and more T-cell exhaustion, with increased CD57 expression in the total population of CD4+ and CD8+ T-cells at different stages of maturation. At 28 weeks’ gestation, MLWH further had a higher percentage of total regulatory T-cells (Tregs). Disrupted CD4+ EM T-cell maturation was noted in HEU infants at birth and 10 weeks of age. They also had a transient increase in CD4+ T-cell activation at 10 weeks but reduced activation of CD8+ T-cells at 10 weeks and six months of age. CD4+ and CD8+ T-cells of HEU infants showed signs of exhaustion at birth and 10 weeks but both had decreased at six months. An increased total percentage of intermediate (IM) monocytes together with increased activation and reduced expression of inhibitory checkpoints in the monocyte subsets were noted in MLWH. No significant differences were observed in the total percentage of classical, IM and non-classical (NC) monocytes between HEU and HUU infants at birth or six months of age, but HEU infants had a lower percentage of total NC monocytes at 10 weeks of age. They also had reduced expression of inhibitory checkpoints at birth and increased monocyte activation at 10 weeks of age.

Apart from interferon-gamma (IFN-γ), HEU infants tended to favour a proinflammatory immune response both before and following whole blood stimulation with lipopolysaccharide and polyinosinic:polycytidylic acid. Although not statistically significant, MLWH had increased plasma levels of interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) and lower IFN-γ and IL-2. Positive correlations were found between maternal IL-6 and IL-8 levels, and infant IL-4 and TGF-β1 at 10 weeks of age, suggesting that a pro-inflammatory maternal milieu does impact infants’ immune profile. No significant differences were, however, observed in cytokine/chemokine concentrations between HEU and HUU infants. A negative association was found between maternal sCD14, and infant length Z-score at birth. Together these findings support the hypothesis that increased maternal immune activation alters basal T-cell maturation, activation, and regulation as well as basal monocyte activation and responsiveness to stimulation of HEU infants at birth and 10 weeks of age. The long-term consequences of these aberrations are still unclear and deserve further study.