Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
FISABIO-Hospital Universitario Dr. Peset, 46017 Valencia, Spain.
Cells. 2021 Feb 16;10(2):410. doi: 10.3390/cells10020410.
Due to medical advances over the past few decades, human immunodeficiency virus (HIV) infection, once a devastatingly mortal pandemic, has become a manageable chronic condition. However, available antiretroviral treatments (cART) cannot fully restore immune health and, consequently, a number of inflammation-associated and/or immunodeficiency complications have manifested themselves in treated HIV-infected patients. Among these chronic, non-AIDS (acquired immune deficiency syndrome)-related conditions, liver disease is one of the deadliest, proving to be fatal for 15-17% of these individuals. Aside from the presence of liver-related comorbidities, including metabolic disturbances and co-infections, HIV itself and the adverse effects of cART are the main factors that contribute to hepatic cell injury, inflammation, and fibrosis. Among the molecular mechanisms that are activated in the liver during HIV infection, apoptotic cell death of hepatocytes stands out as a key pathogenic player. In this review, we will discuss the evidence and potential mechanisms involved in the apoptosis of hepatocytes induced by HIV, HIV-encoded proteins, or cART. Some antiretroviral drugs, especially the older generation, can induce apoptosis of hepatic cells, which occurs through a variety of mechanisms, such as mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR), all of which ultimately lead to caspase activation and cell death.
由于过去几十年的医学进步，人类免疫缺陷病毒（HIV）感染已从一种致命的大流行病转变为一种可控制的慢性疾病。然而，现有的抗逆转录病毒治疗（cART）无法完全恢复免疫健康，因此，许多与炎症相关和/或免疫缺陷的并发症已经在接受治疗的 HIV 感染患者中表现出来。在这些慢性、非艾滋病（获得性免疫缺陷综合征）相关疾病中，肝脏疾病是最致命的疾病之一，证明在这些患者中有 15-17%是致命的。除了存在与肝脏相关的合并症，包括代谢紊乱和合并感染外，HIV 本身和 cART 的不良反应是导致肝细胞损伤、炎症和纤维化的主要因素。在 HIV 感染期间肝脏中激活的分子机制中，肝细胞的凋亡细胞死亡是一个关键的致病因素。在这篇综述中，我们将讨论 HIV、HIV 编码蛋白或 cART 诱导肝细胞凋亡的证据和潜在机制。一些抗逆转录病毒药物，尤其是较旧的一代，会诱导肝细胞凋亡，这是通过多种机制发生的，如线粒体功能障碍、活性氧（ROS）产生增加，以及内质网（ER）应激和未折叠蛋白反应（UPR）的诱导，所有这些最终导致半胱天冬酶的激活和细胞死亡。
