a,d , for the PIMS Study Group Objective: To examine the association between timing of antiretroviral treatment (ART) initiation in HIV-infected women and placental histopathology. Design: A nested substudy in a larger cohort of HIV-infected women which examined the association between ART status and birth outcomes. Methods: Placentas (n ¼ 130) were examined for histopathology from two ART groups: stable (n ¼ 53), who initiated ART before conception and initiating (n ¼ 77), who started ART during pregnancy [median (interquartile range) 15 weeks gestation (11)(12)(13)(14)(15)(16)(17)(18)]. Using binomial regression we quantified associations between ART initiation timing with placental histopathology and pregnancy outcomes. Results: One-third of all placentas were less than 10th percentile weight-for-gestation and there was no significant difference between ART groups. Placental diameter, thickness, cord insertion position and foetal-placental weight ratio were also similar by group. However, placentas from the stable group showed increased maternal vascular malperfusion (MVM) (39.6 vs. 19.4%), and decreased weight (392 vs. 422 g, P ¼ 0.09). MVM risk was twice as high [risk ratios 2.03 (95% confidence interval: 1.16-3.57); P ¼ 0.01] in the stable group; the increased risk remaining significant when adjusting for maternal age [risk ratios 2.04 (95% confidence interval: 1.12-3.72); P ¼ 0.02]. Furthermore, MVM was significantly associated with preterm delivery and low birth weight (P ¼ 0.002 and <0.0001, respectively). Conclusion: Preconception initiation of ART was associated with an increased MVM risk, and may contribute to placental dysfunction. The association between MVM with preterm delivery and low birth weight suggests that a placenta-mediated mechanism likely links the putative association between long-term use of ART and adverse birth outcomes.

During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the infiltration of maternal CD8+ T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. In this study, we characterized the global TCR β-chain profile in human T cells isolated from placentae diagnosed with VUE compared with control and infectious villitis–placentae by immunoSEQ. Immunosequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (CMV, EBV, and influenza A) demonstrated that Ag specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE represents an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk for VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses.

Background Implementation of universal 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 T cell alterations in the placenta contribute to altered immune status in HEU. Methods We analyzed T cells from term placentae decidua and villous tissue and paired cord blood from pregnant women with HIV (PWH) who initiated ART late in pregnancy (n=21) with pregnant women not living with HIV (PWNH) (n=9). Results Placentae from PWH 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. Conclusions T cell homeostatic imbalance in the blood circulation of PWH 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.

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Maternal HIV infection is associated with an increased risk of preterm birth (PTB). However, the mechanisms underlying this increased risk in women with HIV remain poorly understood. In this regard, it is well-established that labor is an inflammatory process and premature activation of the pro-inflammatory signals (associated with labor) can result in preterm labor which can subsequently lead to PTB. HIV infection is known to cause severe immune dysregulation within its host characterized by altered immune profiles, chronic inflammation and eventually, the progressive failure of the immune system. The human placenta comprises different immune cell subsets, some of which play an important role during pregnancy including participating in the inflammatory processes that accompany labor. It is therefore plausible that HIV/antiretroviral therapy (ART)-associated immune dysregulation within the placental microenvironment may underlie the increased risk of PTB reported in women with HIV. Here, we review evidence from studies that point toward the placental origin of spontaneous PTB and discuss possible ways maternal HIV infection and/or ART could increase this risk. We focus on key cellular players in the maternal decidua including natural killer cells, CD4+ T cells including CD4+ regulatory T cells, CD8+ T cells as well as macrophages.

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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.

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