Fig. 1: Pathways of in utero HIV-1 transmission across distinct anatomical sites of the maternal–fetal interface.

HIV-1 crosses the placental barrier primarily in the third trimester through three major routes: (i) exposure to infected amniotic fluid, (ii) direct infection of trophoblasts, and (iii) transcytosis across distinct anatomical sites. a Placental villous tree: HIV-1 infects the placental villous tree by targeting Hofbauer cells (fetal macrophages), villous cytotrophoblasts, and decidual leukocytes. Both cell-free and cell-associated HIV traverse the villi via receptors including CD4, CCR5, CXCR4, and DC-SIGN, with CCR5-tropic R5 strains being preferentially transmitted. HIV-infected PBMCs utilize syncytin-mediated fusion to enter villous tissues, establishing early viral reservoirs detectable as early as 8 weeks gestation. b Fetal intestinal mucosa: HIV particles present in infected amniotic fluid access the fetal gut, where they interact with CD4⁺CCR5⁺ T cells in the intestinal mucosa, leading to activation of Th1 and Th17 responses. However, amniotic fluid is not always infectious, even in mothers with high plasma viral loads, suggesting a context-dependent protective role of the amniotic environment. c Layers of the feto-maternal interface: At the feto-maternal interface, HIV crosses through cell-associated and antibody-mediated transcytosis and direct trophoblast infection, exploiting Fc receptors such as FcRn and Fcγ-RI/III for entry. HIV-infected immune cells, including macrophages and dendritic cells with low or absent CD4 expression, mediate cell-associated transmission, which is more efficient than free-virus transmission. Hofbauer cells can transfer antibody-bound virus to fetal tissues via FcRn, a process blocked by FcRn inhibition. The gestational upregulation of FcRn and viral heterogeneity likely contribute to the increased risk of transmission in late pregnancy and delivery.