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Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1)

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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 (31 March 2020) | Viewed by 63851

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Special Issue Editor

Prof. Dr. Michael Niepmann

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Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany
Interests: translation; replication; miR-122; cellular gene regulation
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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 original research articles will be published in the joint Special Issue in IJMS (https://www.mdpi.com/journal/ijms/special_issues/Hepatitis_C_Virus_Section_2).

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.

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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

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Published Papers (10 papers)

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Review

21 pages, 1889 KiB

Open AccessReview

The Role of the Liver-Specific microRNA, miRNA-122 in the HCV Replication Cycle

by Rasika D. Kunden, Juveriya Q. Khan, Sarah Ghezelbash and Joyce A. Wilson

Int. J. Mol. Sci. 2020, 21(16), 5677; https://doi.org/10.3390/ijms21165677 - 7 Aug 2020

Cited by 45 | Viewed by 6259

Abstract

Hepatitis C virus (HCV) replication requires annealing of a liver specific microRNA, miR-122 to 2 sites on 5′ untranslated region (UTR). While, microRNAs downregulate gene expression by binding to the 3′ untranslated region of the target mRNA, in this case, the microRNA anneals to the 5′UTR of the viral genomes and upregulates the viral lifecycle. In this review, we explore the current understandings of the mechanisms by which miR-122 promotes the HCV lifecycle, and its contributions to pathogenesis. Annealing of miR-122 has been reported to (a) stimulate virus translation by promoting the formation of translationally active internal ribosome entry site (IRES) RNA structure, (b) stabilize the genome, and (c) induce viral genomic RNA replication. MiR-122 modulates lipid metabolism and suppresses tumor formation, and sequestration by HCV may influence virus pathogenesis. We also discuss the possible use of miR-122 as a biomarker for chronic hepatitis and as a therapeutic target. Finally, we discuss roles for miR-122 and other microRNAs in promoting other viruses. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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20 pages, 829 KiB

Open AccessReview

Adaptive Immune Response against Hepatitis C Virus

by Janine Kemming, Robert Thimme and Christoph Neumann-Haefelin

Int. J. Mol. Sci. 2020, 21(16), 5644; https://doi.org/10.3390/ijms21165644 - 6 Aug 2020

Cited by 23 | Viewed by 7005

Abstract

A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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Figure 1

21 pages, 300 KiB

Open AccessReview

Animal Models Used in Hepatitis C Virus Research

by Keith A. Berggren, Saori Suzuki and Alexander Ploss

Int. J. Mol. Sci. 2020, 21(11), 3869; https://doi.org/10.3390/ijms21113869 - 29 May 2020

Cited by 28 | Viewed by 5585

Abstract

The narrow range of species permissive to infection by hepatitis C virus (HCV) presents a unique challenge to the development of useful animal models for studying HCV, as well as host immune responses and development of chronic infection and disease. Following earlier studies in chimpanzees, several unique approaches have been pursued to develop useful animal models for research while avoiding the important ethical concerns and costs inherent in research with chimpanzees. Genetically related hepatotropic viruses that infect animals are being used as surrogates for HCV in research studies; chimeras of these surrogate viruses harboring specific regions of the HCV genome are being developed to improve their utility for vaccine testing. Concurrently, genetically humanized mice are being developed and continually advanced using human factors known to be involved in virus entry and replication. Further, xenotransplantation of human hepatocytes into mice allows for the direct study of HCV infection in human liver tissue in a small animal model. The current advances in each of these approaches are discussed in the present review. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

17 pages, 1162 KiB

Open AccessReview

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

by Kaku Goto, Armando Andres Roca Suarez, Florian Wrensch, Thomas F. Baumert and Joachim Lupberger

Int. J. Mol. Sci. 2020, 21(9), 3057; https://doi.org/10.3390/ijms21093057 - 26 Apr 2020

Cited by 60 | Viewed by 6918

Abstract

Chronic infection with hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC). Novel treatments with direct-acting antivirals achieve high rates of sustained virologic response; however, the HCC risk remains elevated in cured patients, especially those with advanced liver disease. Long-term HCV infection causes a persistent and accumulating damage of the liver due to a combination of direct and indirect pro-oncogenic mechanisms. This review describes the processes involved in virus-induced disease progression by viral proteins, derailed signaling, immunity, and persistent epigenetic deregulation, which may be instrumental to develop urgently needed prognostic biomarkers and as targets for novel chemopreventive therapies. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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12 pages, 1930 KiB

Open AccessReview

Whole Lotta Lipids—From HCV RNA Replication to the Mature Viral Particle

by Hanna Bley, Anja Schöbel and Eva Herker

Int. J. Mol. Sci. 2020, 21(8), 2888; https://doi.org/10.3390/ijms21082888 - 21 Apr 2020

Cited by 28 | Viewed by 5668

Abstract

Replication of the hepatitis C virus (HCV) strongly relies on various lipid metabolic processes in different steps of the viral life cycle. In general, HCV changes the cells’ lipidomic profile by differentially regulating key pathways of lipid synthesis, remodeling, and utilization. In this review, we sum up the latest data mainly from the past five years, emphasizing the role of lipids in HCV RNA replication, assembly, and egress. In detail, we highlight changes in the fatty acid content as well as alterations of the membrane lipid composition during replication vesicle formation. We address the role of lipid droplets as a lipid provider during replication and as an essential hub for HCV assembly. Finally, we depict different ideas of HCV maturation and egress including lipoprotein association and potential secretory routes. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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16 pages, 1279 KiB

Open AccessReview

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

by Pil Soo Sung and Eui-Cheol Shin

Int. J. Mol. Sci. 2020, 21(7), 2583; https://doi.org/10.3390/ijms21072583 - 8 Apr 2020

Cited by 17 | Viewed by 4583

Abstract

When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the IFNL4 genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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33 pages, 3973 KiB

Open AccessReview

Hepatitis C Virus Translation Regulation

by Michael Niepmann and Gesche K. Gerresheim

Int. J. Mol. Sci. 2020, 21(7), 2328; https://doi.org/10.3390/ijms21072328 - 27 Mar 2020

Cited by 31 | Viewed by 7333

Abstract

Translation of the hepatitis C virus (HCV) RNA genome is regulated by the internal ribosome entry site (IRES), located in the 5’-untranslated region (5′UTR) and part of the core protein coding sequence, and by the 3′UTR. The 5′UTR has some highly conserved structural regions, while others can assume different conformations. The IRES can bind to the ribosomal 40S subunit with high affinity without any other factors. Nevertheless, IRES activity is modulated by additional cis sequences in the viral genome, including the 3′UTR and the cis-acting replication element (CRE). Canonical translation initiation factors (eIFs) are involved in HCV translation initiation, including eIF3, eIF2, eIF1A, eIF5, and eIF5B. Alternatively, under stress conditions and limited eIF2-Met-tRNA_i^Met availability, alternative initiation factors such as eIF2D, eIF2A, and eIF5B can substitute for eIF2 to allow HCV translation even when cellular mRNA translation is downregulated. In addition, several IRES trans-acting factors (ITAFs) modulate IRES activity by building large networks of RNA-protein and protein–protein interactions, also connecting 5′- and 3′-ends of the viral RNA. Moreover, some ITAFs can act as RNA chaperones that help to position the viral AUG start codon in the ribosomal 40S subunit entry channel. Finally, the liver-specific microRNA-122 (miR-122) stimulates HCV IRES-dependent translation, most likely by stabilizing a certain structure of the IRES that is required for initiation. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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26 pages, 1658 KiB

Open AccessReview

LncRNAs in HCV Infection and HCV-Related Liver Disease

by Juan P. Unfried and P. Fortes

Int. J. Mol. Sci. 2020, 21(6), 2255; https://doi.org/10.3390/ijms21062255 - 24 Mar 2020

Cited by 35 | Viewed by 5383

Abstract

Long non-coding RNAs (lncRNAs) are transcripts with poor coding capacity that may interact with proteins, DNA, or other RNAs to perform structural and regulatory functions. The lncRNA transcriptome changes significantly in most diseases, including cancer and viral infections. In this review, we summarize the functional implications of lncRNA-deregulation after infection with hepatitis C virus (HCV). HCV leads to chronic infection in many patients that may progress to liver cirrhosis and hepatocellular carcinoma (HCC). Most lncRNAs deregulated in infected cells that have been described function to potentiate or block the antiviral response and, therefore, they have a great impact on HCV viral replication. In addition, several lncRNAs upregulated by the infection contribute to viral release. Finally, many lncRNAs have been described as deregulated in HCV-related HCC that function to enhance cell survival, proliferation, and tumor progression by different mechanisms. Interestingly, some HCV-related HCC lncRNAs can be detected in bodily fluids, and there is great hope that they could be used as biomarkers to predict cancer initiation, progression, tumor burden, response to treatment, resistance to therapy, or tumor recurrence. Finally, there is high confidence that lncRNAs could also be used to improve the suboptimal long-term outcomes of current HCC treatment options. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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17 pages, 757 KiB

Open AccessReview

Hepatitis C Virus Entry: An Intriguingly Complex and Highly Regulated Process

by Che C. Colpitts, Pei-Ling Tsai and Mirjam B. Zeisel

Int. J. Mol. Sci. 2020, 21(6), 2091; https://doi.org/10.3390/ijms21062091 - 18 Mar 2020

Cited by 27 | Viewed by 10098

Abstract

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver disease worldwide. Its tissue and species tropism are largely defined by the viral entry process that is required for subsequent productive viral infection and establishment of chronic infection. This review provides an overview of the viral and host factors involved in HCV entry into hepatocytes, summarizes our understanding of the molecular mechanisms governing this process and highlights the therapeutic potential of host-targeting entry inhibitors. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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25 pages, 6305 KiB

Open AccessReview

The Role of the RNA-RNA Interactome in the Hepatitis C Virus Life Cycle

by Cristina Romero-López and Alfredo Berzal-Herranz

Int. J. Mol. Sci. 2020, 21(4), 1479; https://doi.org/10.3390/ijms21041479 - 21 Feb 2020

Cited by 17 | Viewed by 4322

Abstract

RNA virus genomes are multifunctional entities endowed with conserved structural elements that control translation, replication and encapsidation, among other processes. The preservation of these structural RNA elements constraints the genomic sequence variability. The hepatitis C virus (HCV) genome is a positive, single-stranded RNA molecule with numerous conserved structural elements that manage different steps during the infection cycle. Their function is ensured by the association of protein factors, but also by the establishment of complex, active, long-range RNA-RNA interaction networks-the so-called HCV RNA interactome. This review describes the RNA genome functions mediated via RNA-RNA contacts, and revisits some canonical ideas regarding the role of functional high-order structures during the HCV infective cycle. By outlining the roles of long-range RNA-RNA interactions from translation to virion budding, and the functional domains involved, this work provides an overview of the HCV genome as a dynamic device that manages the course of viral infection. Full article

(This article belongs to the Special Issue Hepatitis C Virus – Molecular Biology, Disease and Treatment (Section 1))

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