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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165677 - 07 Aug 2020

Cited by 42 | Viewed by 5276

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 [...] Read more.

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165644 - 06 Aug 2020

Cited by 18 | Viewed by 6215

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 [...] Read more.

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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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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113869 - 29 May 2020

Cited by 21 | Viewed by 4748

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 [...] Read more.

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093057 - 26 Apr 2020

Cited by 47 | Viewed by 5812

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 [...] Read more.

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082888 - 21 Apr 2020

Cited by 26 | Viewed by 5113

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 [...] Read more.

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072583 - 08 Apr 2020

Cited by 15 | Viewed by 4051

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 [...] Read more.

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072328 - 27 Mar 2020

Cited by 26 | Viewed by 6280

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 [...] Read more.

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062255 - 24 Mar 2020

Cited by 32 | Viewed by 4715

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 [...] Read more.

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062091 - 18 Mar 2020

Cited by 23 | Viewed by 8759

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 [...] Read more.

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041479 - 21 Feb 2020

Cited by 16 | Viewed by 3751

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 [...] Read more.

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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