Tu198 - Disruption of Placental Macrophage Function and Vascular Development by First-line Antiretroviral Drugs: Rescue Potential of Exogenous FXIIIA1

Abstract Text:

Background: We previously reported that antiretroviral treatment (ART) in pregnant individuals living with HIV is associated with a 2-fold increased risk of maternal vascular malperfusion. We also found lower levels of coagulation factor XIIIA1 (FXIIIA1) in placental Hofbauer Cells (HBCs), which correlated with pre-term birth, particularly when ART was initiated pre-conception. We hypothesize that ART disrupts HBC function through FXIIIA1, impairing placental vascularization.

Methods: We employed a HUVEC angiogenesis assay to investigate FXIIIA1 and its inhibitor ZED1301. Placenta-like macrophages were generated by stimulating primary human monocytes with M-CSF and IL-10. We tested ARV cytotoxicity, determining IC50 and physiological concentrations for co-culture experiments with HUVECs and macrophages.

Results: FXIIIA1 (5 μg/ml) enhanced branching and tubular formation in the HUVEC model (p=0.04). Inhibition of FXIIIA1 with ZED1301 reduced branch thickness in a dose-dependent manner. The important role placental macrophages in this process was confirmed when placenta-like macrophages promoted vascular growth without conventional endothelial growth factors (p=0.0016). However, when pre-treated for 24h with dolutegravir or a Tenofovir + 3TC +Efavirenz combination, these macrophages no longer supported angiogenesis, showing reduced tube formation and network connectivity (p=0.0013). A similar effect was observed when ARVs were added directly to the HUVEC model. Exogenous FXIIIA1 rescued angiogenesis impaired by ARVs.

Conclusion: These findings suggest that pre-conception ART may impair placental vascularization by disrupting HBC function through FXIIIA1. This provides a potential mechanism by which ART may contribute to adverse birth outcomes and highlights the need for further investigation into adjunctive therapies to counteract these effects.