尽管高活性抗逆转录病毒疗法(HAART)已将人类免疫缺陷病毒(HIV)的感染从即将死亡的诊断转变为慢性疾病,未发展为获得性免疫缺陷综合征(AIDs)的HIV阳性患者仍然患有高的心脏功能障碍和纤维化。不管病毒载量和CD计数,HIV相关心肌病(HIVAC)仍然导致HIV患者的高死亡率和发病率。虽然这是一个很好的临床现象,HIVAC的分子机制尚不清楚。在这次审查中,我们巩固,分析,并讨论了自噬与HIVAC交叉的研究现状。多项研究已经将自噬的各种调节因子和功能成分的失调与HIV感染联系起来,无论病毒进入的方式如何。即,冠状动脉,心腔,或者心包空间.HIV蛋白,包括负调节因子(Nef),糖蛋白120(gp120),和反式激活因子(Tat),已显示与II型微管相关蛋白-1β轻链(LC3-II)相互作用,Rubiquitin,SQSTM1/p62,Rab7,自噬特异性基因7(ATG7),和溶酶体相关膜蛋白1(LAMP1),所有对正常自噬至关重要的分子。HIV感染还可以通过改变三磷酸腺苷(ATP)的产生和平衡来诱导线粒体生物能的失调,线粒体活性氧(ROS),和钙。这些变化改变了线粒体的质量和形态,通常会触发自噬以清除功能失调的细胞器。然而,艾滋病毒感染也引发自噬功能障碍,这些异常的线粒体积聚并导致心肌功能障碍。同样,使用HAART,叠氮胸苷和阿巴卡韦,已被证明通过在抗逆转录病毒治疗期间诱导异常自噬来诱导心脏功能障碍和纤维化。相反,研究表明,增加自噬可以减少功能失调的线粒体的积累,恢复心肌细胞的功能。有趣的是,雷帕霉素,哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂,还显示通过调节自噬相关蛋白来减少HIV诱导的细胞毒性,使其成为具有治疗HIVAC潜力的非抗病毒药物。在这次审查中,我们综合这些发现,以更好地理解自噬在HIVAC中的作用,并讨论本研究揭示的潜在药理靶点.
Although highly active antiretroviral therapy (HAART) has changed infection with human immunodeficiency virus (HIV) from a diagnosis with imminent mortality to a chronic illness, HIV positive patients who do not develop acquired immunodeficiency syndrome (AIDs) still suffer from a high rate of cardiac dysfunction and fibrosis. Regardless of viral load and CD count, HIV-associated
cardiomyopathy (HIVAC) still causes a high rate of mortality and morbidity amongst HIV patients. While this is a well characterized clinical phenomena, the molecular mechanism of HIVAC is not well understood. In this review, we consolidate, analyze, and discuss current research on the intersection between autophagy and HIVAC. Multiple studies have linked dysregulation in various regulators and functional components of autophagy to HIV infection regardless of mode of viral entry, i.e., coronary, cardiac chamber, or pericardial space. HIV proteins, including negative regulatory factor (Nef), glycoprotein 120 (gp120), and transactivator (Tat), have been shown to interact with type II microtubule-associated protein-1 β light chain (LC3-II), Rubiquitin, SQSTM1/p62, Rab7, autophagy-specific gene 7 (ATG7), and lysosomal-associated membrane protein 1 (LAMP1), all molecules critical to normal autophagy. HIV infection can also induce dysregulation of mitochondrial bioenergetics by altering production and equilibrium of adenosine triphosphate (ATP), mitochondrial reactive oxygen species (ROS), and calcium. These changes alter mitochondrial mass and morphology, which normally trigger autophagy to clear away dysfunctional organelles. However, with HIV infection also triggering autophagy dysfunction, these abnormal mitochondria accumulate and contribute to myocardial dysfunction. Likewise, use of HAART, azidothymidine and Abacavir, have been shown to induce cardiac dysfunction and fibrosis by inducing abnormal autophagy during antiretroviral therapy. Conversely, studies have shown that increasing autophagy can reduce the accumulation of dysfunctional mitochondria and restore cardiomyocyte function. Interestingly, Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has also been shown to reduce HIV-induced cytotoxicity by regulating autophagy-related proteins, making it a non-antiviral agent with the potential to treat HIVAC. In this review, we synthesize these findings to provide a better understanding of the role autophagy plays in HIVAC and discuss the potential pharmacologic targets unveiled by this research.