Molecular Insights into HIV-associated Cardiac Dysfunction

Antiretroviral therapy (ART) in human immunodeficiency virus (HIV) improved life expectancy in people living with HIV (PLWH) but cardiac diseases have emerged as a leading cause of death in this population. There is a notable increase in diastolic dysfunction and HF with preserved ejection fraction (HFpEF) attributed to the altered metabolic milieu seen in PLWH on ART. However, the specific role(s) that HIV itself, and/or ART may have on the cardiomyocyte phenotype is unknown. We investigated molecular pathways altered in cardiomyocytes in vitro in response to serum from ART-naïve and after ART-treated patients. Cardiomyocytes were treated for 24 hours with serum obtained longitudinally from HIV patients before and after receiving ART for 6 months. RNA sequencing revealed that differences between pre- and post-treatment with ART were related to processes involving cell death, cardiomyocyte calcium handling, and adverse remodeling. Apoptotic death was increased in cardiomyocytes treated with serum obtained from ART naïve HIV patients whereas those treated with serum from the same patients 6 months after ART presented changes in calcium-handling proteins and profibrotic markers, indicating altered contraction and relaxation, and adverse remodeling. These findings demonstrate altered molecular pathways in cardiomyocytes in response to active viremia and ART.人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）感染者接受抗逆转录病毒治疗（Antiretroviral Therapy, ART）后，预期寿命显著提升，但心脏疾病已成为该人群的首要死亡诱因。接受ART治疗的HIV感染者体内代谢微环境发生重塑，致使舒张功能障碍（diastolic dysfunction）与射血分数保留的心力衰竭（Heart Failure with Preserved Ejection Fraction, HFpEF）的发病率显著升高。然而，HIV本身以及/或ART对心肌细胞表型（cardiomyocyte phenotype）的具体调控作用仍未明确。本研究以ART初治患者及接受ART治疗后的患者血清为研究对象，体外探究其对心肌细胞分子通路的影响。实验中，我们采用HIV患者在接受6个月ART治疗前后纵向采集的血清处理心肌细胞，处理时长为24小时。RNA测序（RNA sequencing）结果显示，ART治疗前后的血清处理组间差异主要聚焦于细胞死亡、心肌细胞钙处理以及不良心肌重构相关的生物学过程。经ART初治HIV患者血清处理的心肌细胞，其细胞凋亡（apoptotic death）水平显著升高；而用同一患者接受ART治疗6个月后的血清处理的心肌细胞，则出现钙处理蛋白与促纤维化标志物（profibrotic markers）的表达异常，提示心肌收缩与舒张功能紊乱及不良心肌重构。本研究结果证实，心肌细胞的分子通路会因活动性病毒血症（active viremia）与ART治疗而发生显著改变。