Hopkins Sam, Gallay Philippe A
Department of Clinical Research, Autoimmune Technologies, New Orleans, LA 70112 USA.
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Biochim Biophys Acta. 2015 Oct;1850(10):2103-10. doi: 10.1016/j.bbagen.2014.11.011. Epub 2014 Nov 18.
Tremendous progress has been made in the past 20 years in understanding the roles played by immunophilins, and in particular the cyclophilins, in supporting the replication cycles of human viruses. A growing body of genetic and biochemical evidence and data from clinical trials confirm that cyclophilins are essential cofactors that contribute to establishing a permissive environment within the host cell that supports the replication of HIV-1 and HCV. Cyclophilin A regulates HIV-1 replication kinetics and infectivity, modulates sensitivity to host restriction factors, and cooperates in the transit of the pre-integration complex into the nucleus of infected cells. Cyclophilin A is an essential cofactor whose expression supports HCV-specific RNA replication in human hepatocytes.
Peptidyl-prolyl isomerase inhibitors have been used in clinical trials to validate cyclophilins as antiviral targets for the treatment of HIV-1 and Chronic Hepatitis C virus infection and as molecular probes to identify the roles played by immunophilins in supporting the replication cycles of human viruses.
This review summarizes emerging research that defines the functions of immunophilins in supporting the replication cycles of HIV-1, HCV, HBV, coronaviruses, and other viral pathogens and describes new information that suggests a role for immunophilins in regulating innate immune responses against chronic viral infection.
The dependence on cyclophilins by evolutionarily distinct viruses for accomplishing various steps in replication such as viral entry, initiation of genomic nucleic acid replication, viral genome uncoating, nuclear import and nuclear entry, emphasizes the potential of cyclophilin inhibitors as therapeutic agents. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
在过去20年里，人们在了解亲免素尤其是亲环素在支持人类病毒复制周期中所起的作用方面取得了巨大进展。越来越多的遗传学和生物化学证据以及临床试验数据证实，亲环素是必不可少的辅助因子，有助于在宿主细胞内建立支持HIV-1和HCV复制的允许环境。亲环素A调节HIV-1的复制动力学和感染性，调节对宿主限制因子的敏感性，并协同前整合复合物进入受感染细胞的细胞核。亲环素A是一种必不可少的辅助因子，其表达支持HCV特异性RNA在人肝细胞中的复制。
肽基脯氨酰异构酶抑制剂已用于临床试验，以验证亲环素作为治疗HIV-1和慢性丙型肝炎病毒感染的抗病毒靶点，以及作为分子探针来确定亲免素在支持人类病毒复制周期中所起的作用。
本综述总结了新兴研究，这些研究定义了亲免素在支持HIV-1、HCV、HBV、冠状病毒和其他病毒病原体复制周期中的功能，并描述了新信息，这些信息表明亲免素在调节针对慢性病毒感染的先天免疫反应中发挥作用。
进化上不同的病毒在复制的各个步骤（如病毒进入、基因组核酸复制起始、病毒基因组脱壳、核输入和核进入）中对亲环素的依赖，强调了亲环素抑制剂作为治疗剂的潜力。本文是名为“脯氨酸定向折叠酶：细胞信号催化剂和药物靶点”的特刊的一部分。
