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

Abstract

Human immunodeficiency virus (HIV) infection is characterized by chronic, systemic immune activation. It is unclear how this affects the immune system of infants born to mothers living with HIV (MLWH). The current study assessed whether maternal HIV status and in utero antiretroviral therapy (ART) exposure impact infant T-cell and monocyte activation and regulation, as well as monocyte responsiveness to stimulation at birth and early infancy. T-cell and monocyte activation and expression of immune checkpoint molecules were characterized by means of flow cytometry. Pro- and anti-inflammatory cytokine/chemokine profiles were assessed using a suspension bead array assay. Seventy-one pregnant MLWH and 77 mothers not living with HIV (MNLWH) were recruited at 22 weeks’ gestation, and mother-infant pairs were followed until 6 months postpartum. MLWH had higher percentages of CD4+ and CD8+ T-cells expressing programmed cell death protein-1 (PD-1) and a higher percentage of regulatory T-cells (Tregs). HIV-exposed-but-uninfected (HEU) infants displayed disrupted CD4+ T-cell maturation with an increased number of CD8+ T-cells expressing PD-1 at the time of birth and increased T-cell exhaustion at 10 weeks of age. Higher levels of monocyte activation were observed in MLWH with increased numbers of classical (CL) monocytes expressing CCR2 and CD80. An increased percentage of CL monocytes expressing CCR2 and CD80 was noted in HEU infants at the time of birth, which persisted at 10 weeks of age. Significantly higher levels of C-reactive protein (CRP) and non-significantly higher levels of interleukin (IL)-6 and tumor necrosis factor-alpha were observed in MLWH, indicative of hyperactivated innate inflammation. HEU infants had persistently increased levels of IL-8 and transforming growth factor (TGF)-β1, and lower levels of IL-10, IFN-γ, and CRP. The latter might be secondary to cotrimoxazole use in the HEU infants while the altered cytokine levels might be indicative of altered immune programing. In summary, this cohort study showed that maternal HIV status has a transient effect on basal infant T-cell and monocyte activation, regulation, and monocyte responsiveness, which dissipates at 6 months of age, while altered cytokine levels persisted.