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

While antiretroviral therapy (ART) has extended the life of people living with HIV (PLWH), they experience accelerated development of hypertension and cardiovascular disease (CVD) compared to seronegative individuals. However, the etiology and 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 function and hypertension. We utilized a Tg26 transgenic mouse model ubiquitously expressing 7/9 viral proteins. These mice display increased blood pressure (BP) and enhanced neurogenic control of BP (BP response to ganglionic blockade) as well as impaired endothelial vasorelaxation in aorta and mesenteric arteries in both sexes. Bone marrow transplant (BMT) from Tg26 mice into WT (Tg26->WT) increased systolic BP and impaired endothelium dependent relaxation in conduit and resistance vessels (P<0.05), a precursor to hypertension. To identify the immune cell subtype responsible for the CVD, thoracic aortas from WT male and female mice were co-cultured with either WT or Tg26 primary CD3+ Tcells. Vessels exposed to Tg26 Tcells displayed impaired endothelial relaxation versus WT (P<0.05). Vessels incubated in Tg26 CD4+ Tcells, the main target of HIV, also yielded endothelial dysfunction and 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 1a (IL-1a) in Tg26 CD3+ T cells (P<0.05). Similarly, Tg26->WT BMT increased plasma IL-1a levels (P<0.1), while Abatacept decreased plasma IL-1a levels in intact Tg26 mice (P<0.05). Treatment with anti-IL-1a antibody abolished Tcell-mediated endothelial dysfunction and primary human microvascular endothelial cells (hMVEC) treated with IL-1a for 24 hours increased ROS mediated DNA damage (8-OHdG), leading us to investigate the source of vascular ROS. Quantitative RT-PCR of the IL-1a exposed hMVEC displayed increases in NADPH oxidase NOX1, NOXO1, and NOX4 while BMT aortas had increased in NOX1, NOXO1, and NOXA1 and inhibition of NOX1 via GKT771 ex vivo restored vasorelaxation. Additionally, anti-IL-1a restored vasorelaxion in intact Tg26 mice. Ultimately, we found that Tcells expressing viral proteins promote the production of IL-1a, increasing endothelial NOX1 and ROS production, leading to endothelial dysfunction, which in addition to sympatho-activation promote hypertension. 1R01HL147639, 21PRE830396, 19EIA34760167 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.