Background
The number of HIV-1-exposed uninfected (HEU) children remains on the rise. Studies showed that HEU children are at increased risk for preterm delivery, infectious morbidity, immune abnormalities, and impaired growth; yet there are gaps in understanding of how in utero HIV-1 and antiretroviral drug (ARVs) exposures may impact HEU children’s health across their lifespan. ARVs effects on maternal health or gross structural fetal outcomes have been widely studied. However, there is a critical knowledge gap of the effects of ARVs on placental health, a key regulator of fetal development and pregnancy outcomes. Herein, the effects of dolutegravir (DTG) on placenta were evaluated as the drug’s association with abnormal vasculature was previously reported. As hypoxia-inducible factor 1-alpha (HIF-1α) is a key regulator of vascular development, we investigated whether genetic deficits in HIF-1α could influence DTG-linked placental vascular abnormalities in heterozygous HIF-1α knockout mice.
Methods
Placenta specific heterozygous HIF-1α (HIF-1αf/-) conditional knockout (Cre/LoxP) mice were generated. C57BL/6J mice served as controls. Pregnant mice were administered daily with DTG (50 mg/kg) or vehicle (control) starting at gestation day (GD) 0.5 using oral gavage. Pregnant mice were scanned at GD 16.5 by 7T MRI to generate T2 relaxation time maps of placentas. At GD 17.5, placenta tissues were harvested for pharmacokinetic (PK) and pathological tests.
Results
PK tests showed an average of 5005 ng/gm of DTG levels in placentas of both HIF-1αf/- and C57BL/6J mice. In HIF-1αf/- pregnant mice, significant increase in T2 relaxation times was quantified in placentas exposed to DTG compared to placentas exposed to vehicle, indicating vasculature alterations. In parallel, compared to the vehicle exposed group, histopathological tests confirmed enlargement of the placental labyrinth region in DTG exposed animals. Increased HIF-1α protein expression in DTG-exposed placenta tissues cross-validated both T2 maps and histology data. Furthermore, a significant decrease in weights and crown-rump lengths of embryos was noted in the DTG-exposed group. In contrast, in C57BL/6J pregnant mice, DTG-exposure did not lead to alterations in T2 maps, HIF-1α levels, and placental or embryo morphology.
Conclusions
An association between HIF-1α and DTG-induced placental vascular changes was observed. Genetic or co-morbidities-inducing HIF-1α deficiency may increase the risk for DTG-regimen-affected placental development.