CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

Placenta-like macrophages were generated by stimulating primary human monocytes with M-CSF and IL-10. We tested HIV antiretroviral drugs cytotoxicity, determining IC 50 and physiological concentrations for co-culture experiments with HUVECs and placenta-like macrophages. Results: Activated 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 of 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 antiretroviral drugs were added directly to the HUVEC model. Exogenous FXIIIA1 partially rescued impaired angiogenesis by HIV antiretroviral drugs. Conclusions: These findings suggest that pre-conception HIV antiretroviral treatment may impair placental vascularization by disrupting placental macrophage function through FXIIIA1. This provides a potential mechanism by which long-term antiretroviral treatment elevates the risk of maternal vascular malperfusion and placental insufficiency. This highlights the need for adjunctive therapies to counteract the long-term effect of HIV antiretroviral treatment on placental vascularization. Micah Summerlin 1 , Christine A. Adalikwu 1 , Aida M. Jemal 1 , Baojin Yao 1 , Emma G. Foster 1 , Surendra K. Shukla 2 , Nicole Liu 1 , Anushka Sajja 1 , Balasrinivasa R. Sajja 1 , Yutong Liu 1 , Lynda K. Harris 1 , Benson Edagwa 1 , Howard Gendelman 1 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 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-1α f/- ) 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 T 2 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-1α f/- and C57BL/6J mice. In HIF-1α f/- pregnant mice, significant increase in T 2 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 T 2 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 T 2 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.

1002 Immune Markers During Pregnancy and Birth Outcomes in South African WLH Thokozile R. Malaba 1 , Clive Gray 2 , Tariq Webber 2 , Hlengiwe Madlala 1 , Berenice Alinde 1 , Landon Myer 1 , Marie-Louise Newell 3 , for the PIMS Study Group 1 University of Cape Town, Cape Town, South Africa, 2 Stellenbosch University, Cape Town, South Africa, 3 University of Southampton, Southampton, UK Background: There are few insights into the immunological predictors of pregnancy outcomes, including preterm delivery (PTD) and small-for gestational age (SGA), in women living with HIV (WLH). Methods: We followed ART-eligible pregnant WLH attending primary care in Cape Town from their first antenatal visit through to delivery. C-reactive protein (CRP), interferon gamma-induced protein 10 (IP10), and serum amyloid A (SAA) levels were measured at ≥3 antenatal time points: baseline (<24 weeks [visit 1]), 2 weeks post-ART initiation (if starting ART during pregnancy [visit 2]), 28w [visit 3] and 34w [visit 4]gestation. Group-based trajectory modelling (GBTM) identified distinct biomarker trajectories throughout pregnancy. Modified Poisson regression assessed associations between these trajectories and PTD (<37 weeks) and SGA (<10th percentile for gestational age [GA]), adjusting for age, BMI and ART timing (before vs during pregnancy). Results: In 505 women (median age 30y; median GA 14w; 23% nulliparous) with a livebirth, 48% (n=241) initiated ART preconception (84% TDF+XTC+EFV, 8% PI-based regimen) and 52% (n=264) initiated during pregnancy (97% TDF+XTC+EFV, 1% PI-based regimens). Median CRP and SAA levels over time did not differ by ART status, but IP-10 levels were higher in women initiating ART during pregnancy than in preconception ART initiators (Fig1a). We identified 4 distinct IP-10 trajectories, with one group (6.5% of women) showing an atypical pattern, with IP-10 levels steadily increasing throughout pregnancy (traj 2) compared to stable (traj 1) or decreasing (traj 3 and 4) (Fig1b). Those with atypical IP-10 trajectories had significantly higher PTD risk (ARR2.08, 95% CI1.03-4.19) than other groups. No associations were observed between CRP and SAA with PTD, and none between the three biomarker trajectories and SGA. Conclusions: Atypical increases in IP-10 during pregnancy which would indicate increasing inflammation were associated with an increased risk of PTD, but not SGA. Findings suggest IP-10 could be used as a biomarker identifying pregnant women with HIV at higher risk for PTD and inform clinical management. The figure, table, or graphic for this abstract has been removed. 1003 Antiretroviral Drugs Disrupt Macrophage Function and Vascular Development Doty B. A. Ojwach 1 , Daniel Simpkin 2 , Justin Duruanyanwu 2 , Tariq Webber 1 , Portia Manngo 1 , Berenice Alinde 3 , Paola Campagnolo 2 , Siamon Gordon 4 , Fernando Martinez Estrada 2 , Clive Gray 1 1 Stellenbosch University, Cape Town, South Africa, 2 University Surrey, Guildford, UK, 3 University of Cape Town, Cape Town, South Africa, 4 Oxford University, Oxford, UK Background: We previously reported in the Prematurity Immunology in Mothers living with HIV and their infants Study (PIMS), that antiretroviral treatment 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, which correlated with pre-term birth, particularly when HIV antiretroviral treatment was initiated pre-conception. We hypothesize that HIV antiretroviral treatment disrupts Hofbauer cell function through FXIIIA1, impairing placental vascularization. Methods: We employed a primary Human Umbilical Vein Endothelial Cells (HUVEC) angiogenesis assay to investigate FXIIIA1 and its inhibitor ZED1301.

Poster Abstracts

1004 Antiretroviral Drugs Affect the Placental Vasculature

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CROI 2025 319