SUNY Downstate Health Sciences University, New York, NY, USA.
Institute of Molecular Medicine, Feinstein Institute for Medical Research and Zucker School of Medicine at Hofstra-Northwell, Manhasset, NY, USA.
FEBS J. 2021 Oct;288(19):5586-5597. doi: 10.1111/febs.15677. Epub 2020 Dec 31.
HIV-associated nephropathy (HIVAN) remains a concern among untreated HIV patients, notably of African descent, as patients can reach end-stage renal disease within 3 years. Two variants (G1 and G2) of the APOL1 gene, common in African populations to protect against African sleeping sickness, have been associated with an increased risk of several glomerular disorders including HIVAN, hypertension-attributed chronic kidney disease, and idiopathic focal segmental glomerulosclerosis and are accordingly named renal risk variants (RRVs). This review examines the mechanisms by which APOL1 RRVs drive glomerular injury in the setting of HIV infection and their potential application to patient management. Innate antiviral mechanisms activated by chronic HIV infection, especially those involving type 1 interferons, are of particular interest as they have been shown to upregulate APOL1 expression. Additionally, the downregulation of miRNA 193a (a repressor of APOL1) is also associated with the upregulation of APOL1. Interestingly, glomerular damage affected by APOL1 RRVs is caused by both loss- and gain-of-function changes in the protein, explicitly characterizing these effects. Their intracellular localization offers a further understanding of the nuances of APOL1 variant effects in promoting renal disease. Finally, although APOL1 variants have been recognized as a critical genetic player in mediating kidney disease, there are significant gaps in their application to patient management for screening, diagnosis, and treatment.
HIV 相关性肾病（HIVAN）仍然是未接受治疗的 HIV 患者（尤其是非洲裔患者）关注的问题，因为这些患者可能在 3 年内发展为终末期肾病。APOL1 基因的两种变体（G1 和 G2）在非洲人群中很常见，可以预防非洲昏睡病，与几种肾小球疾病（包括 HIVAN、高血压相关的慢性肾脏病和特发性局灶节段性肾小球硬化症）的风险增加有关，因此被称为肾脏风险变体（RRV）。这篇综述探讨了 APOL1 RRV 在 HIV 感染背景下导致肾小球损伤的机制及其在患者管理中的潜在应用。慢性 HIV 感染激活的先天抗病毒机制，特别是涉及 I 型干扰素的机制，特别有趣，因为它们已被证明可上调 APOL1 的表达。此外，miRNA 193a（APOL1 的抑制剂）的下调也与 APOL1 的上调有关。有趣的是，APOL1 RRV 引起的肾小球损伤是由该蛋白的功能丧失和获得性变化引起的，明确描述了这些作用。它们的细胞内定位进一步理解了 APOL1 变体在促进肾脏疾病中的作用的细微差别。最后，尽管 APOL1 变体已被认为是介导肾脏疾病的关键遗传因素，但在将其应用于患者的筛查、诊断和治疗方面仍存在显著差距。
