Maternal Inflammation Likely Drives Impaired Immune Responses to Respiratory Syncytial Virus in HIV-Exposed Uninfected Infants

Background Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection and a major contributor to morbidity and mortality in HIV-exposed, uninfected (HEU) infants. The mechanisms underlying HEU infants’ increased susceptibility to RSV are unclear. Methods We recruited pregnant women with and without HIV, plus HEU and HIV-unexposed (HUU) children at 12-18 months of age and collected peripheral and cord blood. We measured innate immune responses of infants to RSV using an in vitro model of human respiratory infection. These responses were correlated with markers of inflammation in maternal and cord blood. We also incubated HUU cord blood cells in plasma from women living with HIV (WLHIV) to recapitulate the RSV-specific responses in HEU cord blood cells. Results We enrolled 30 WLHIV, 61 HIV-negative women, 19 HEU and 20 HUU children. At birth, HEU infants demonstrated lower expression of IL-12 by dendritic cells (p<0.0001) and IFNγ by natural killer (NK) cells (p=0.007); the difference in IL-12 expression persisted to 12-18 months of age (p=0.015). WLHIV had high concentrations of multiple inflammatory molecules in peripheral blood; these correlated inversely with infant RSV-specific immune responses. Incubation of cord blood cells from HUU infants in maternal plasma from WLHIV significantly lowered RSV-specific NK cytotoxicity and antigen-presenting cell activation compared to incubation in HIV-negative maternal plasma. Discussion Maternal inflammation is a likely driver of innate immune dysregulation in HEU infants and predisposes to an increased susceptibility to RSV infection.