Pregnancy Gestation Impacts on HIV-1-Specific Granzyme B Response and Central Memory CD4 T Cells

Abstract

Pregnancy induces alterations in peripheral T-cell populations with both changes in subset frequencies and anti-viral responses found to alter with gestation. In HIV-1 positive women anti-HIV-1 responses are associated with transmission risk, however detailed investigation into both HIV-1-specific memory responses associated with HIV-1 control and T-cell subset changes during pregnancy have not been undertaken. In this study we aimed to define pregnancy and gestation related changes to HIV-1-specific responses and T-cell phenotype in ART treated HIV-1 positive pregnant women. Eleven non-pregnant and 24 pregnant HIV-1 positive women were recruited, peripheral blood samples taken, fresh cells isolated, and compared using ELISpot assays and flow cytometry analysis. Clinical data were collected as part of standard care, and non-parametric statistics used. Alterations in induced IFNγ, IL-2, IL-10, and granzyme B secretion by peripheral blood mononuclear cells in response to HIV-1 Gag and Nef peptide pools and changes in T-cell subsets between pregnant and non-pregnant women were assessed, with data correlated with participant clinical parameters and longitudinal analysis performed. Cross-sectional comparison identified decreased IL-10 Nef response in HIV-1 positive pregnant women compared to non-pregnant, while correlations exhibited reversed Gag and Nef cytokine and protease response associations between groups. Longitudinal analysis of pregnant participants demonstrated transient increases in Gag granzyme B response and in the central memory CD4 T-cell subset frequency during their second trimester, with a decrease in CD4 effector memory T cells from their second to third trimester. Gag and Nef HIV-1-specific responses diverge with pregnancy time-point, coinciding with relevant T-cell phenotype, and gestation associated immunological adaptations. Decreased IL-10 Nef and both increased granzyme B Gag response and central memory CD4 T cells implies that amplified antigen production is occurring, which suggests a period of compromised HIV-1 control in pregnancy.

Does Precision-Based Medicine Hold the Promise of a New Approach to Predicting and Treating Spontaneous Preterm Birth?

“…Even with treatment and subsequent immune reconstitution of CD4 T cells, the effects of chronic viral infection potentiate the proinflammatory environment, and some elements of immune dysregulation persist. Specifically, in pregnancy, the result is an upregulation of cytotoxic decidual NK cells and both decidual and peripheral CD8 T cells and an Increase in the proinflammatory subsets of (M1) monocytes and macrophages with cytokine (IL-6, TNFα and IL-1b) and phagocytic immune functions [41,42]. Moreover, both decidual and peripheral T helper subsets are altered, but specifically, at the maternal-fetal interface, there is a skewed T helper cell profile that results in further proinflammatory cytokine release [41].…”

Lights and Shadows of TORCH Infection Proteomics

“…Among pregnant and non-pregnant women, there were changes in the secretion of IFNγ, IL-2, IL-10, and granzyme B in peripheral blood. On the other hand, HIV-1 positive pregnant women showed a decrease in the IL-10 response (anti-inflammatory cytokine) [ 86 ]. IL-10 and IL-4 play an important role in protecting the fetus from local or systemic inflammation through inhibition of lymphokine-activated NK [ 87 ].…”

T cell Homeostatic Imbalance in Placentae from Women with HIV in the absence of Vertical Transmission

“…Initiation of ART has been shown to augment HIV-specific CD4+ T cell responses, but normalization of the CD4:CD8 T cell ratio does not occur in a large proportion of HIV positive individuals[4]. In pregnant women living with HIV (PWLWH), pregnancy is not associated with HIV disease progression, although it has been associated with functional impairment of systemic effector T cells and an overall altered response against HIV control[5,6].…”