Submit a Manuscript: http://www.wjgnet.com/esps/ World J Hepatol 2016 January 8; 8(1): 9-35 Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 1948-5182 (online) DOI: 10.4254/wjh.v8.i1.9 © 2016 Baishideng Publishing Group Inc. All rights reserved. TOPIC HIGHLIGHT 2016 Advances in Hepatitis C Virus Chaperones in hepatitis C virus infection Ronik Khachatoorian, Samuel W French Ronik Khachatoorian, Samuel W French, Department of First decision: September 8, 2015 Pathology and Laboratory Medicine, David Geffen School of Revised: October 1, 2015 Medicine at University of California, Los Angeles, CA 90095, Accepted: December 17, 2015 United States Article in press: December 18, 2015 Published online: January 8, 2016 Samuel W French, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, United States Samuel W French, UCLA AIDS Institute, David Geffen School Abstract of Medicine at University of California, Los Angeles, CA 90024, The hepatitis C virus (HCV) infects approximately 3% of United States the world population or more than 185 million people worldwide. Each year, an estimated 350000-500000 Author contributions: Khachatoorian R conducted an extensive deaths occur worldwide due to HCV-associated diseases article search, identified all relevant articles, developed the including cirrhosis and hepatocellular carcinoma. HCV is outline of the review article, prepared all the drafts, revised the accepted manuscript, and approved the article to be published; the most common indication for liver transplantation in French SW contributed to the design and writing of the manu­ patients with cirrhosis worldwide. HCV is an enveloped script, reviewed and edited the drafts, revised the accepted manu­ RNA virus classified in the genus Hepacivirus in the script, and approved the article to be published. Flaviviridae family. The HCV viral life cycle in a cell can be divided into six phases: (1) binding and inter- Supported by NIH R01DK090794, SWF. nalization; (2) cytoplasmic release and uncoating; (3) viral polyprotein translation and processing; (4) RNA Conflict-of-interest statement: The authors declare no conflict genome replication; (5) encapsidation (packaging) and of interest. assembly; and (6) virus morphogenesis (maturation) and secretion. Many host factors are involved in the Open-Access: This article is an open­access article which was HCV life cycle. Chaperones are an important group of selected by an in­house editor and fully peer­reviewed by external reviewers. It is distributed in accordance with the Creative host cytoprotective molecules that coordinate numerous Commons Attribution Non Commercial (CC BY­NC 4.0) license, cellular processes including protein folding, multimeric which permits others to distribute, remix, adapt, build upon this protein assembly, protein trafficking, and protein work non­commercially, and license their derivative works on degradation. All phases of the viral life cycle require different terms, provided the original work is properly cited and chaperone activity and the interaction of viral proteins the use is non­commercial. See: http://creativecommons.org/ with chaperones. This review will present our current licenses/by­nc/4.0/ knowledge and understanding of the role of chaperones in the HCV life cycle. Analysis of chaperones in HCV Correspondence to: Samuel W French, MD, PhD, Associate infection will provide further insights into viral/host Professor, Department of Pathology and Laboratory Medicine, interactions and potential therapeutic targets for both David Geffen School of Medicine at University of California, HCV and other viruses. 10833 Le Conte Avenue, Los Angeles, CA 90095, United States. [email protected] Telephone: +1­310­2672795 Key words: Hepatitis C; Hepatitis C virus; Chaperones; Fax: +1­310­2672058 Heat shock proteins; Viral life cycle Received: April 29, 2015 © The Author(s) 2016. Published by Baishideng Publishing Peer-review started: May 7, 2015 Group Inc. All rights reserved. WJH|www.wjgnet.com 9 January 8, 2016|Volume 8|Issue 1| Khachatoorian R et al . Chaperones and HCV frameshift near the beginning of the core protein coding Core tip: Interaction of viral proteins with host cha- sequence. The F protein has been implicated in the perones is critical for the hepatitis C viral (HCV) life regulation of protein degradation, inhibition of apoptosis, cycle. Some of these chaperones, such as cyclophilins and immunoregulation[24-31]. have been studied in detail recently and have led to The 5’ non-coding region (NCR) of the viral genome the advent of new therapies for HCV infection with high success rates. Further investigation of the role of possesses an IRES, a cis-acting element found in chaperones in the viral life cycle may allow for deve- some host RNA transcripts as well as in viruses that lopment of novel therapies both for HCV and related allows ribosomal translation initiation to occur internally viruses. within a transcript in lieu of 5’ 7-methylguanylate cap- dependent translation[12,32]. The HCV viral life cycle in a cell can be divided into six phases: (1) binding and Khachatoorian R, French SW. Chaperones in hepatitis C virus internalization; (2) cytoplasmic release and uncoating; infection. World J Hepatol 2016; 8(1): 9­35 Available from: (3) viral polyprotein translation and processing; (4) RNA URL: http://www.wjgnet.com/1948­5182/full/v8/i1/9.htm DOI: genome replication; (5) encapsidation (packaging) and http://dx.doi.org/10.4254/wjh.v8.i1.9 assembly; and (6) virus morphogenesis (maturation) and secretion[33] (Figure 1). The viral life cycle begins with the attachment of the enveloped virion to the cell followed by entry, INTRODUCTION which is mediated by interaction of the E1 and E2 glycoproteins in the viral membrane with a number of The hepatitis C virus (HCV) infects approximately hepatocyte cell surface receptors and proteins which 3% of the world population or more than 185 million include the low-density lipoprotein receptor (LDLR), people worldwide[1,2]. While infection is less prevalent glycosaminoglycans (GAGs), CD81, scavenger receptor in developed countries including North America, other [1] B1 (SR-B1), claudin 1, occludin, and the cholesterol areas face prevalence rates as high as 3.5% or more . [34] absorption receptor Niemann-Pick C1-like 1 . Sub- Each year, an estimated 350000-500000 deaths occur sequently, the viral particle is internalized through worldwide due to HCV-associated diseases[1-3]. HCV is clathrin-mediated endocytosis or an alternative clathrin- mainly responsible for liver transplantation in patients [4-6] independent pathway after which, the viral and cellular with cirrhosis worldwide . Furthermore, HCV is the membranes fuse through acidification of the endosomal most common chronic bloodborne pathogen in the compartment, and the core-encapsidated viral genome United States affecting 1.5% of the population and is is released into the cytosol, uncoated, and subsequently the major etiologic factor responsible for the recent [35,36] [5,7-9] translated . The resulting polyprotein is cleaved with doubling of hepatocellular carcinoma . the help of the cellular proteases signalase and signal HCV is an enveloped RNA virus classified in the peptide peptidase and the viral proteases NS2-NS3 genus Hepacivirus in the Flaviviridae family. It possesses and NS3-NS4A[37]. Viral genome replication is carried an approximately 9.6 kb positive-sense RNA genome out by NS5B utilizing a negative-sense viral genome that is translated as a single polypeptide approximately intermediate[38]. New virions are assembled at the sites [10,11] 3000 amino acids in length . It is subsequently of cytosolic lipid droplets in the vicinity of endoplasmic proteolytically cleaved into 10 viral proteins including reticulum (ER) membrane where core protein enca- the structural proteins core, E1, and E2 as well as the psidates the viral genome followed by budding of the non-structural (NS) proteins p7, NS2, NS3, NS4A, nascent virion into the lumen of ER[39]. The virions follow [12] NS4B, NS5A and NS5B . Core is the viral nucleocapsid the Golgi-dependent secretory pathway during which protein that encapsidates the viral genome in the virion. they undergo maturation by addition of lipid components E1 and E2 are glycoproteins on the viral envelope that significantly decreasing their buoyant density[40,41]. Finally are involved in receptor-mediated viral entry. p7 is an the mature virions are secreted through exocytosis[42]. integral membrane ion channel also called viroporin In order to establish successful infection, HCV that functions to protect virions from acidification during depends on numerous host factors during its entire life [13] maturation by allowing protons to flow . NS2, NS3, and cycle. In addition to performing virus-specific functions NS4A are the viral proteases, while NS4B is a helicase. such as viral genome replication and virion assembly, NS5A, a 56-59 kDa multifunctional phosphoprotein, HCV proteins alter cellular metabolism, critical signaling lacks any known enzymatic activity, is a component of pathways, and organellar morphology and function to the viral replicase complex, and has been implicated in establish persistent infection and to escape the immune regulation of HCV genome replication, internal ribosomal responses. Accumulation of misfolded viral proteins entry site (IRES)-mediated viral protein translation, in the ER leads to ER stress and the unfolded protein and infectious