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

Abstract

BackgroundImplementation of Option B+ antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of HIV-exposed uninfected children (HEU), who remain vulnerable to morbidities. Here, we investigated whether altered immune status in HEU originates in the placenta.MethodsWe analyzed T cells from term placentae decidua and villous tissue and paired cord blood from pregnant women living with HIV (PWLWH) who initiated ART late in pregnancy (n=21) with HIV negative controls (n=9).ResultsPlacentae from PWLWH showed inverted CD4:CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentae. CD8+ T cells in the fetal capillaries, which were of fetal origin, positively correlated with maternal plasma viraemia prior to ART initiation, implying that imbalanced T cells persisted throughout pregnancy. Additionally, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood, but was not observed in the maternal decidua.ConclusionT cell homeostatic imbalance in the blood circulation of PWLWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission.Lay SummaryThe effective prevention of HIV transmission during pregnancy with the rollout of antiretroviral therapy (ART) has resulted in increased numbers of HIV-exposed uninfected children (HEU). These children are vulnerable to infections and health problems and they have altered cellular immune systems at birth. We investigated whether these immune alterations may originate in the placenta, as this fetal organ maintains life during pregnancy. Do immune alterations in the newborn child originate in the placenta? After collecting placentae at term from pregnant women living with HIV (PWLWH), who started ART in the third trimester (n=21) and from HIV negative controls (n=9), we isolated T cells from dissected placental tissue and matching cord blood. Placentae from PWLWH showed inverted CD4:CD8 ratios in the placenta and cord blood with higher numbers of CD8+ T cells in the fetal part of the placenta. These CD8+ T cells mirrored events in the blood circulation of the mother and the altered balance of T cell immunity in the PWLWH was reflected in the placenta. Accordingly, the placenta may be a pivotal link between HIV-induced maternal immune changes and altered immunity in newborn infants in the absence of vertical transmission.

Preterm Birth in Women With HIV: The Role of the Placenta

“…It is now wellestablished that acute HIV infection is associated with expansion of the effector systemic CD8+ T cell pool and although these cell numbers decline slightly following the initiation of antiretroviral therapy (ART), they remain elevated in most individuals even after years of treatment (107,108). A similar occurrence is noted in the decidua, as it has been recently shown that decidual CD8+ T cells are increased in placentae from women with HIV at term and these proportions correlate with maternal viral load pre-ART (15). Women with high viral loads prior to ART initiation are more likely to have increased CD8+ T cells in the maternal decidua at delivery.…”

“…In addition to these robust immune responses in early pregnancy, the uptake of maternal antiretroviral therapy (ART) has been shown to significantly reduce the risk of vertical transmission, even if taken in the third trimester ( 45 ). However, even in the absence of vertical transmission, maternal HIV infection is associated with an altered immune landscape in the decidua and villous tissue ( 15 ). In addition, placentae from women with HIV have been shown to have increased features of placental insufficiency including maternal vascular malperfusion, and features of acute and chronic inflammation ( 12 ).…”

“…CD4+ T cells have been well-characterized in HIV infection and in fact one of the hallmark features of HIV infection is the gradual loss of CD4+ T cells and the imbalance of CD4+ T cell homeostasis due to the fact that HIV preferentially infects and destroys CD4+ T cells ( 132 ). It has also been recently shown that HIV infection is associated with a dysregulated T cell landscape in the maternal decidua; women with HIV have lower proportions of CD4+ T cells compared to women with no HIV ( 15 ). The depletion of CD4+ T cells in HIV infection is mainly thought to be due to direct HIV infection.…”

“…These patterns of injury have further been associated with adverse birth outcomes such as PTB and available evidence links poor placental function to compromised fetal development ( 13 , 14 ). Women with HIV manifest an altered placental T cell profile where the decidua appears to mirror the systemic circulation during HIV infection characterized by a dysregulated CD4:CD8 T cell ratio and this dysregulation positively correlates with maternal viral load ( 15 ).…”