Host-Viral Interactions at the Maternal-Fetal Interface. What We Know and What We Need to Know

Abstract

In humans, the hemochorial placenta is a unique temporary organ that forms during pregnancy to support fetal development, gaseous exchange, delivery of nutrition, removal of waste products, and provides immune protection, while maintaining tolerance to the HLA-haploidentical fetus. In this review, we characterize decidual and placental immunity during maternal viral (co)-infection with HIV-1, human cytomegalovirus (HCMV), and Zika virus. We discuss placental immunology, clinical presentation, and epidemiology, before characterizing host susceptibility and cellular tropism, and how the three viruses gain access into specific placental target cells. We describe current knowledge on host-viral interactions with decidual and stromal human placental macrophages or Hofbauer cells, trophoblasts including extra villous trophoblasts, T cells, and decidual natural killer (dNK) cells. These clinically significant viral infections elicit both innate and adaptive immune responses to control replication. However, the three viruses either during mono- or co-infection (HIV-1 and HCMV) escape detection to initiate placental inflammation associated with viral transmission to the developing fetus. Aside from congenital or perinatal infection, other adverse pregnancy outcomes include preterm labor and spontaneous abortion. In addition, maternal HIV-1 and HCMV co-infection are associated with impaired fetal and infant immunity in postnatal life and poor clinical outcomes during childhood in exposed infants, even in the absence of vertical transmission of HIV-1. Given the rapidly expanding numbers of HIV-1-exposed uninfected infants and children globally, further research is urgently needed on neonatal immune programming during maternal mono-and co-infection. This review therefore includes sections on current knowledge gaps that may prompt future research directions. These gaps reflect an emerging but poorly characterized field. Their significance and potential investigation is underscored by the fact that although viral infections result in adverse consequences in both mother and developing fetus/newborn, antiviral and immunomodulatory therapies can improve clinical outcomes in the dyad.

Maternal and birth outcomes in pregnant people with and without HIV in the Western Cape, South Africa

“…However, we also identified a more nuanced relationship between ART duration and fetal growth, whereby ART started in the second half of pregnancy (< 20 weeks duration) and ART started preconception (> 40 weeks duration) were both associated with increased LBW and VLBW compared to ART started during the first half of pregnancy (20-< 40 weeks duration). For pregnancies where ART is only started later, the fetus is exposed to a perturbed in utero environment for substantially longer, compared to ART started early in pregnancy in which the maternal immune system has potentially stabilized by the time fetal weight gain is expected to accelerate later in pregnancy [ 30 ]. ART duration >40 weeks, that is mostly preconception, was not as detrimental as late pregnancy ART initiation (<20 weeks duration) but was still significantly associated with LBW and VLBW compared to early pregnancy ART initiation (20-<40 weeks duration), likely after the time of conception.…”

Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor

“…MDMX is predominantly expressed (Fig. 3C and D) on Hofbauer cells (HC) [36][37][38][39][40] that are targets of Zika and other viruses [41]. Strong MDMX staining was limited to the cytoplasm of HC, easily identified within the villous stroma, some within stromal channels (Fig.…”

Macrophages: Key Cellular Players in HIV Infection and Pathogenesis

“…Since more recent studies have shown that purified Kupffer cells are highly permissive to HIV-1 infection in vitro, some authors propose that these resident macrophages could play important role in driving hepatic inflammation and fibrosis in infected patients (for review, see [ 42 ]). Similarly, HIV-1 infection of the placental Hofbauer macrophages was recognized early as they are central mediators of vertical mother-to-child HIV-1 transmission during pregnancy (for reviews, see [ 43 , 44 , 45 , 46 ]). Furthermore, it was recently reported that Hofbauer cells isolated from early- and mid-gestation are rather resistant to HIV-1 replication in vitro, compared to the higher susceptibility of term-gestation Hofbauer cells [ 47 ].…”