Abstract P181: Tcell Derived Hiv Proteins Promote Oxidative Stress, Endothelial Dysfunction And Hypertension Via Interleukin 1a-mediated Mechanisms In Mice.

Abstract

Antiretroviral therapy (ART) has markedly extended the life of people living with HIV (PLWH). However, PLWH now experience accelerated development of hypertension and cardiovascular disease (CVD), the etiology of which, including the individual contributions of ART and repressed viral infection, remain ill-defined. While ART prevents viral replication, viral reservoirs persist, and viral proteins remain in the circulation leading us to hypothesize that Tcell-derived HIV proteins contribute to endothelial dysfunction and hypertension. We utilized the Tg26 transgenic mouse model which ubiquitously express 7/9 viral proteins and reported increased blood pressure (BP) and impaired endothelium-dependent relaxation (EDR) in aorta and mesenteric arteries in both sexes. Bone marrow transplant (BMT) from Tg26 mice into WT (Tg26->WT) increased BP (WT->WT: 141.6 Tg26->WT 160.3 mmHg; P<0.05) and impaired EDR in conduit and resistance vessels (P<0.05). To determine whether Tcells, the main target of HIV, are responsible for CVD in Tg26 mice, thoracic aortas from WT male and female mice were co-cultured with either WT or Tg26 primary CD3+ Tcells, and yielded endothelial dysfunction. Moreover, inhibition of Tcell activation via Abatacept treatment in intact Tg26 mice lowered BP, restored vasorelaxation and reduced sympatho-activation to WT levels in Tg26 mice (P<0.05). A cytokine panel revealed increased production of interleukin 1α (IL-1α) in Tg26 CD3+ Tcells and plasma of Tg26->WT BMT (P<0.05). Abatacept decreased plasma IL-1α levels in intact Tg26 mice (P<0.05). Treatment with anti-IL-1α antibody abolished Tcell-mediated endothelial dysfunction and primary human microvascular endothelial cells (hMVEC) treated with IL-1α for 24 hours increased ROS mediated DNA damage (8-OHdG). IL-1α exposed hMVEC displayed increases in NOX1, NOXO1, and NOX4 while BMT aortas showed increased NOX1, NOXO1, and NOXA1. Inhibition of NOX1 via GKT771 ex vivo restored vasorelaxation. Additionally, anti-IL-1α restored vasorelaxation and BP in intact Tg26 mice. Ultimately, we found that Tcells expressing viral proteins produce high IL-1α levels which increase endothelial NOX1 expression and ROS production, leading to endothelial dysfunction and hypertension