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Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 2)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 11879

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Special Issue Editor

Prof. Dr. Michael Niepmann

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Guest Editor

Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany
Interests: translation; replication; miR-122; cellular gene regulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hepatitis C Virus (HCV) preferentially replicates in the human liver and frequently causes chronic infection, often leading to cirrhosis and liver cancer. HCV is an enveloped virus classified in the genus Hepacivirus in the family Flaviviridae and has a single-stranded RNA genome of positive orientation. Both hepatocyte surface receptors and the liver-specific microRNA-122 contribute to HCV hepatotropism, and the HCV life cycle is closely linked to the lipid metabolism of hepatocytes. The HCV RNA genome is translated by virtue of an internal ribosome entry site. After a pilot round of genome translation, replication factories called “membranous webs” are formed in the cytoplasm, which are the sites of genome replication. During RNA genome synthesis, the error-prone viral replicase provides a high mutation rate in the genome, allowing the virus to easily escape from host immune responses and treatment. Moreover, viral proteins interfere with the immune response in order to establish an ongoing chronic infection “under the radar” of the host, a strategy to ensure its spread among host individuals not aware of the infection, even at the time of effective anti-viral treatment. While such treatment does not protect against repeated infection, vaccines are under development.

In this Special Issue, we would like to provide comprehensive overviews over important aspects of the molecular events in the HCV life cycle, disease development and the current state of HCV treatment.
Potential topics include, without being limited to, the following:

Introduction to Hepatitis C Virus
HCV phylogeny and molecular evolution
Cell culture model systems used in HCV research
Animal model systems used in HCV research
HCV model systems
HCV protein structure
Entry receptors and events
Regulation of HCV translation
The structure of viral replication complexes
Molecular biology of viral RNA replication, cis-signals and protein factors
Long-range RNA-RNA interactions and switches in the viral life cycle
Functions of the liver-specific microRNA-122 in the HCV replication cycle
Non-coding RNAs in HCV replication (including lncRNAs)
cis-Determinants of viral RNA encapsidation during assembly
Virus assembly and release, lipid metabolism
Innate immune responses to HCV infection and viral counter-measures
Adaptive immune response and viral escape
Pathogenesis, cirrhosis and Hepatocellular Carcinoma (HCC)
Clinical HCV treatment: state of the art, problems and perspectives
Vaccine development

Accepted review papers will be published in the joint Special Issue in IJMS (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/Hepatitis_C_Virus_Section_1).

Prof. Dr. Michael Niepmann
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Entry Receptors
HCV genome model systems
Cell culture systems
Animal models
Translation
Replication
Lipid metabolism
Assembly
Immune Response
Hepatocellular Carcinoma (HCC)
Direct-acting antivirals (DAAs)
Treatment
Escape mutants

Published Papers (4 papers)

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Research

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24 pages, 2712 KiB

Open AccessArticle

A Novel Cis-Acting RNA Structural Element Embedded in the Core Coding Region of the Hepatitis C Virus Genome Directs Internal Translation Initiation of the Overlapping Core+1 ORF

by Niki Vassilaki, Efseveia Frakolaki, Katerina I. Kalliampakou, Panagiotis Sakellariou, Ioly Kotta-Loizou, Ralf Bartenschlager and Penelope Mavromara

Int. J. Mol. Sci. 2020, 21(18), 6974; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186974 - 22 Sep 2020

Cited by 1 | Viewed by 2707

Abstract

Hepatitis C virus (HCV) genome translation is initiated via an internal ribosome entry site (IRES) embedded in the 5′-untranslated region (5′UTR). We have earlier shown that the conserved RNA stem-loops (SL) SL47 and SL87 of the HCV core-encoding region are important for viral genome translation in cell culture and in vivo. Moreover, we have reported that an open reading frame overlapping the core gene in the +1 frame (core+1 ORF) encodes alternative translation products, including a protein initiated at the internal AUG codons 85/87 of this frame (nt 597–599 and 603–605), downstream of SL87, which is designated core+1/Short (core+1/S). Here, we provide evidence for SL47 and SL87 possessing a novel cis-acting element that directs the internal translation initiation of core+1/S. Firstly, using a bicistronic dual luciferase reporter system and RNA-transfection experiments, we found that nucleotides 344–596 of the HCV genotype-1a and -2a genomes support translation initiation at the core+1 frame AUG codons 85/87, when present in the sense but not the opposite orientation. Secondly, site-directed mutagenesis combined with an analysis of ribosome–HCV RNA association elucidated that SL47 and SL87 are essential for this alternative translation mechanism. Finally, experiments using cells transfected with JFH1 replicons or infected with virus-like particles showed that core+1/S expression is independent from the 5′UTR IRES and does not utilize the polyprotein initiation codon, but it requires intact SL47 and SL87 structures. Thus, SL47 and SL87, apart from their role in viral polyprotein translation, are necessary elements for mediating the internal translation initiation of the alternative core+1/S ORF. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 2))

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22 pages, 3653 KiB

Open AccessArticle

Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication

by Gesche K. Gerresheim, Carolin S. Hess, Lyudmila A. Shalamova, Markus Fricke, Manja Marz, Dmitri E. Andreev, Ivan N. Shatsky and Michael Niepmann

Int. J. Mol. Sci. 2020, 21(18), 6955; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186955 - 22 Sep 2020

Cited by 2 | Viewed by 2865

Abstract

Hepatitis C virus (HCV) infects liver cells and often causes chronic infection, also leading to liver cirrhosis and cancer. In the cytoplasm, the viral structural and non-structural (NS) proteins are directly translated from the plus strand HCV RNA genome. The viral proteins NS3 to NS5B proteins constitute the replication complex that is required for RNA genome replication via a minus strand antigenome. The most C-terminal protein in the genome is the NS5B replicase, which needs to initiate antigenome RNA synthesis at the very 3′-end of the plus strand. Using ribosome profiling of cells replicating full-length infectious HCV genomes, we uncovered that ribosomes accumulate at the HCV stop codon and about 30 nucleotides upstream of it. This pausing is due to the presence of conserved rare, inefficient Wobble codons upstream of the termination site. Synonymous substitution of these inefficient codons to efficient codons has negative consequences for viral RNA replication but not for viral protein synthesis. This pausing may allow the enzymatically active replicase core to find its genuine RNA template in cis, while the protein is still held in place by being stuck with its C-terminus in the exit tunnel of the paused ribosome. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 2))

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Review

Jump to: Research

11 pages, 6218 KiB

Open AccessReview

Autophagy in HCV Replication and Protein Trafficking

by Ja Yeon Kim Chu and Jing-hsiung James Ou

Int. J. Mol. Sci. 2021, 22(3), 1089; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031089 - 22 Jan 2021

Cited by 12 | Viewed by 2561

Abstract

Autophagy is a catabolic process that is important for maintaining cellular homeostasis. It is also known to possess other functions including protein trafficking and anti-microbial activities. Hepatitis C virus (HCV) is known to co-opt cellular autophagy pathway to promote its own replication. HCV regulates autophagy through multiple mechanisms to control intracellular protein and membrane trafficking to enhance its replication and suppress host innate immune response. In this review, we discuss the current knowledge on the interplay between HCV and autophagy and the crosstalk between HCV-induced autophagy and host innate immune responses. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 2))

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20 pages, 718 KiB

Open AccessReview

HCV Glycoprotein Structure and Implications for B-Cell Vaccine Development

by Luisa J. Ströh and Thomas Krey

Int. J. Mol. Sci. 2020, 21(18), 6781; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186781 - 16 Sep 2020

Cited by 9 | Viewed by 3240

Abstract

Despite the approval of highly efficient direct-acting antivirals in the last decade Hepatitis C virus (HCV) remains a global health burden and the development of a vaccine would constitute an important step towards the control of HCV. The high genetic variability of the viral glycoproteins E1 and E2, which carry the main neutralizing determinants, together with their intrinsic structural flexibility, the high level of glycosylation that shields conserved neutralization epitopes and immune evasion using decoy epitopes renders the design of an efficient vaccine challenging. Recent structural and functional analyses have highlighted the role of the CD81 receptor binding site on E2, which overlaps with those neutralization epitopes within E2 that have been structurally characterized to date. This CD81 binding site consists of three distinct segments including “epitope I”, “epitope II” and the “CD81 binding loop”. In this review we summarize the structural features of the HCV glycoproteins that have been derived from X-ray structures of neutralizing and non-neutralizing antibody fragments complexed with either recombinant E2 or epitope-derived linear peptides. We focus on the current understanding how neutralizing antibodies interact with their cognate antigen, the structural features of the respective neutralization epitopes targeted by nAbs and discuss the implications for informed vaccine design. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 2))

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