In 1989, one in four (25%) infants born to women living with HIV were infected; by the age of 2 years, there was 25% mortality among them due to HIV. These and other pieces of data prompted the development of interventions to offset vertical transmission, including the landmark Pediatric AIDS Clinical Trial Group Study (PACTG 076) in 1994. This study reported a 67.5% reduction in perinatal HIV transmission with prophylactic antenatal, intrapartum, and postnatal zidovudine. Numerous studies since then have provided compelling evidence to further optimize interventions, such that annual transmission rates of 0% are now reported by many health departments in the US and elimination has been validated in several countries around the world. Despite this success, the elimination of HIV’s vertical transmission on the global scale remains a work in progress, limited by socioeconomic factors such as the prohibitive cost of antiretrovirals. Here, we review some of the key trials underpinning the development of guidelines in the US as well as globally, and discuss the evidence through a historic lens.

In 2019, >90% of new HIV infections in infants globally occurred vertically. Studies suggest intrauterine transmission most often occurs in the third trimester; however, there are no mechanistic studies to support these observations. We therefore obtained early/mid-gestation and term placentae from 20 HIV/Hepatitis B/CMV negative women. Isolated primary placental macrophages (Hofbauer cells [HCs]) were exposed to HIV-1_BaLand/or interferon (IFN)-α, IFN-β, IFN-λ1, and RIG-I-like receptor (RLR) agonists. qRT-PCR, FACS, ELISA, Luminex, and Western blot analyses determined expression of activation markers, co-receptors, viral antigen, cytokines, antiviral genes, and host proteins. Early gestation HCs express higher levels of CCR5 and exhibit a more activated phenotype. Despite downregulation of CCR5, term HCs were more susceptible to HIV replication. Early gestation HCs displayed a more activated phenotype than term HCs and HIV exposure lead to the further up-regulation of T-cell co-stimulatory and MHC molecules. Limited HIV replication in early/mid gestation HCs was associated with increased secretion of anti-inflammatory cytokines, chemokines, and a more robust antiviral immune response. In contrast, term HCs were more susceptible to HIV replication, associated with dampening of IFN-induced STAT1 and STAT2 protein activation. Treatment of early/mid gestation and term HCs, with type I IFNs or RLR agonists reduced HIV replication, underscoring the importance of IFN and RLR signaling in inducing an antiviral state. Viral recognition and antiviral immunity in early gestation HCs may preventin uteroHIV infection, whereas diminished antiviral responses at term can facilitate transmission. Defining mechanisms and specific timing of vertical transmission are critical for the development of specific vaccines and antiviral therapeutics to prevent new HIV infections in children globally.

The placenta is a unique organ with various immunological and endocrinological roles that modulate maternal and fetal physiology to promote maternal-fetal tolerance, pregnancy maintenance, and parturition at term. During pregnancy, the hormone prolactin (PRL) is constitutively secreted by the placenta and is necessary for implantation, progesterone support, fetal development, and overall immune modulation. While PRL is essential for pregnancy, studies suggest that elevated levels of serum PRL (hyperprolactinemia) are associated with adverse pregnancy outcomes, including miscarriage, preterm birth, and preeclampsia. However, there is a lack of mechanistic studies to support these observations. Here we investigated the impact of elevated levels of PRL on placental cells and evaluated PRL effects on the JAK2/STAT5 inflammatory signaling cascade. Elevated levels of exogenous PRL enhances PRL and PRL-receptor expression, along with JAK2/STAT5 signaling in primary decidual mononuclear cells and the placental trophoblast cell line, JEG-3. Following PRL exposure, the STAT5 isoform, STAT5B, is preferentially activated and there is a significant upregulation in the secretion of pro-inflammatory cytokines, IL-6 and IL-1β. This inflammatory cascade is supported via PRL-induced reduction of SOCS1 and SOCS2. Furthermore, LPS exacerbates PRL expression and JAK2/STAT5 signaling, leading to increased secretion of IL-6 and TNF-α. These results highlight the inflammatory roles of elevated PRL at the maternal-fetal interface, underscoring the need for further mechanistic studies to elucidate its functions in pregnancy.

Black and African American women in the United States experience disproportionately high rates of maternal and infant mortality and morbidity, including placenta-mediated complications such as preeclampsia, preterm birth, and miscarriage. These inequities arise from the interaction of social and environmental conditions with biological pathways that become embedded over the life course, with the placenta serving as a central mediator. In this review, we examine how placental biology integrates genetic variation, epigenetic regulation, paternal contributions, immune processes, and lived social context to shape pregnancy outcomes. We synthesize evidence showing that placental dysfunction, particularly immune dysregulation driven by infectious, environmental, and psychosocial stressors, contributes to placenta-mediated complications with disproportionate impacts among African American women. We highlight how reliance on racial categories in U.S. biomedical research can obscure biological inference and argue for ancestry-informed approaches, alongside self-identified ethnicity, to disentangle inherited genetic variation from socially patterned exposures. Surveying published genome-wide association studies, we show that underrepresentation of African-ancestry populations remains a major constraint on discovery and translation in pregnancy genomic research. We further describe how placental epigenetic mechanisms link socioeconomic and environmental exposures to fetal development, placental aging, and long-term maternal–child health. Finally, we discuss how pregnancy and placental datasets remain sparse and fragmented, and consider how machine-learning approaches may improve pregnancy risk prediction when designed with equity in mind, by integrating placental multi-omics, ancestry-aware genomics, clinical data, and social determinants. Together, this review positions the placenta as a critical interface through which structural inequities shape maternal–fetal health and identifies priorities for more inclusive and equitable research and health care.

Elucidating how HIV and cytomegalovirus (CMV) co-infection in pregnancy disrupts immune homeostasis at the maternal–fetal interface can provide a foundation for developing intervention strategies to improve infant and maternal health. Of importance is the identification of infant immune dysregulation, especially in HIV-exposed uninfected newborns (HEU). Although vertical transmission of HIV has been substantially mitigated by antiretroviral treatment, the incidence of adverse birth outcomes remains significantly higher in these infants than in those born to mothers without HIV. We hypothesize that the immune status of mothers during pregnancy impacts upon the placenta, in turn affecting infant immunity. We explore this hypothesis by examining data from key studies and clinical cohorts, aiming to ‘join the dots’ to form a body of knowledge to catalyse development of more comprehensive studies. Our narrative represents a thought piece incorporating events around HIV and CMV during the antenatal period, the impact of maternal immunity and immune events in the placenta, and how these factors produce a ‘knock-on’ effect on infant immune ontogeny and susceptibility to poor health. We introduce the concept of vertical transmission of inflammation, where in the absence of viral transmission, the effects of a maternal inflammatory milieu could profoundly impact birth and infant outcomes via placental dysfunction. This article is part of the discussion meeting issue ‘The indirect effects of cytomegalovirus infection: mechanisms and consequences’.