Exploring the immunological impact of HIV-1 on pregnancy

Abstract

The immune system alters during pregnancy to support a semi-allogeneic fetus until term labour. Disruption in the timing of pregnancy is associated with excessive immune activation, loss of leukocyte populations and alterations in cell subset ratios in peripheral blood, but with unreliable prediction of preterm labour, longitudinal observation has not been possible. HIV-1 positive women have a higher incidence of pregnancy complications indicating disruption to their immune system affects key populations involved in the maintenance of pregnancy. This project determined the cross-sectional and longitudinal phenotypic and functional pathways that differ in the peripheral immune systems of HIV-1 negative and positive pregnancies through comparison with HIV-1 negative and positive non-pregnant women. Pregnant women were recruited at Chelsea and Westminster Hospital, blood drawn in each trimester and at delivery, and peripheral blood mononuclear cells extracted for flow cytometric phenotypic analysis and functional assays including anti-viral memory response, NK activation and intracellular cytokine staining. Cross-sectional comparison of groups demonstrated that both innate and adaptive cell branches were disrupted in the HIV-1 positive women; dendritic cell populations were skewed, natural killer cell maturation was driven towards anergy, lower CD4 T-cell frequency and effector T-cell populations dominated in the HIV-1 positive participants. Longitudinal comparison highlighted gestation specific alterations in regulatory T cells associated with increased suppressive capacity were lost in the HIV-1 positive group, and a continuous inflation of highly differentiated T-cell memory subsets was found. Decreased IL-10 response to Nef and transiently increased response to Gag peptides were found, and NK and T-cell markers of activation increased with gestation. However, longitudinal reconstitution was also observed in monocyte, DC, NK and T-cell populations, implying pregnancy may partly counter HIV-1-mediated chronic activation. Furthermore, comparison of HIV-1 negative and positive pregnant immune phenotypes highlighted differentiation pathways potentially key to pregnancy regulation of the immune system.