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686 KiB

Open AccessArticle

Roles of ITPA and IL28B Genotypes in Chronic Hepatitis C Patients Treated with Peginterferon Plus Ribavirin

by Tatsuo Miyamura, Tatsuo Kanda, Shingo Nakamoto, Shuang Wu, Xia Jiang, Makoto Arai, Keiichi Fujiwara, Fumio Imazeki and Osamu Yokosuka

Viruses 2012, 4(8), 1264-1278; https://doi.org/10.3390/v4081264 - 14 Aug 2012

Cited by 20 | Viewed by 8056

Abstract

It has been reported that inosine triphosphatase (ITPA) gene variants protect against ribavirin-induced anemia in patients treated for chronic hepatitis C. IL28B variants also influence the treatment response of peginterferon plus ribavirin treatment in these patients. In the present study, we examined how [...] Read more.

It has been reported that inosine triphosphatase (ITPA) gene variants protect against ribavirin-induced anemia in patients treated for chronic hepatitis C. IL28B variants also influence the treatment response of peginterferon plus ribavirin treatment in these patients. In the present study, we examined how ITPA and IL28B genotypes have clinical impacts on treatment-induced hematotoxicities and treatment response in HCV-infected patients treated with peginterferon plus ribavirin. ITPA genotypes (rs1127354 and rs6051702) and IL28B genotype (rs8099917) were determined by TaqMan SNP assay. We compared clinical background, treatment course and treatment response in terms of these genotypes. Only IL28B rs8099917 major type could predict sustained virological response. ITPA rs1127354 major type leads to significantly greater ribavirin-induced anemia than ITPA rs1127354 minor type between days 0 and 84. We noticed that IL28B rs8099917 minor genotype was associated with higher reduction of neutrophils and platelets. ITPA rs1127354 is useful for the prediction of ribavirin-induced anemia in the early phase after the commencement of peginterferon plus ribavirin treatment and IL28B rs8099917 is useful for the prediction of sustained virological response. Use of the combination of these two genotypes could lead to safe and effective treatment of chronic hepatitis C patients. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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1896 KiB

Open AccessArticle

RNA-Sequencing Analysis of 5' Capped RNAs Identifies Many New Differentially Expressed Genes in Acute Hepatitis C Virus Infection

by Neven Papic, Christopher I. Maxwell, Don A. Delker, Shuanghu Liu, Bret S. E. Heale and Curt H. Hagedorn

Viruses 2012, 4(4), 581-612; https://doi.org/10.3390/v4040581 - 16 Apr 2012

Cited by 42 | Viewed by 12136

Abstract

We describe the first report of RNA sequencing of 5' capped (Pol II) RNAs isolated from acutely hepatitis C virus (HCV) infected Huh 7.5 cells that provides a general approach to identifying differentially expressed annotated and unannotated genes that participate in viral-host interactions. [...] Read more.

We describe the first report of RNA sequencing of 5' capped (Pol II) RNAs isolated from acutely hepatitis C virus (HCV) infected Huh 7.5 cells that provides a general approach to identifying differentially expressed annotated and unannotated genes that participate in viral-host interactions. We identified 100, 684, and 1,844 significantly differentially expressed annotated genes in acutely infected proliferative Huh 7.5 cells at 6, 48, and 72 hours, respectively (fold change ≥ 1.5 and Bonferroni adjusted p-values < 0.05). Most of the differentially expressed genes (>80%) and biological pathways (such as adipocytokine, Notch, Hedgehog and NOD-like receptor signaling) were not identified by previous gene array studies. These genes are critical components of host immune, inflammatory and oncogenic pathways and provide new information regarding changes that may benefit the virus or mediate HCV induced pathology. RNAi knockdown studies of newly identified highly upregulated FUT1 and KLHDC7B genes provide evidence that their gene products regulate and facilitate HCV replication in hepatocytes. Our approach also identified novel Pol II unannotated transcripts that were upregulated. Results further identify new pathways that regulate HCV replication in hepatocytes and suggest that our approach will have general applications in studying viral-host interactions in model systems and clinical biospecimens. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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Review

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1631 KiB

Open AccessReview

Hepatitis C Virus-Induced Mitochondrial Dysfunctions

by Charlène Brault, Pierre L. Levy and Birke Bartosch

Viruses 2013, 5(3), 954-980; https://doi.org/10.3390/v5030954 - 21 Mar 2013

Cited by 53 | Viewed by 17685

Abstract

Chronic hepatitis C is characterized by metabolic disorders and a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that lead in the long term to hepatocellular carcinoma. Many lines of evidence suggest that mitochondrial dysfunctions, including modification of metabolic [...] Read more.

Chronic hepatitis C is characterized by metabolic disorders and a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that lead in the long term to hepatocellular carcinoma. Many lines of evidence suggest that mitochondrial dysfunctions, including modification of metabolic fluxes, generation and elimination of oxidative stress, Ca²⁺ signaling and apoptosis, play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory, probably due to the use of artificial expression and replication systems. In vivo studies are hampered by the fact that innate and adaptive immune responses will overlay mitochondrial dysfunctions induced directly in the hepatocyte by HCV. Thus, the molecular aspects underlying HCV-induced mitochondrial dysfunctions and their roles in viral replication and the associated pathology need yet to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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218 KiB

Open AccessReview

Hepatitis C Virus in American Indian/Alaskan Native and Aboriginal Peoples of North America

by Julia D. Rempel and Julia Uhanova

Viruses 2012, 4(12), 3912-3931; https://doi.org/10.3390/v4123912 - 19 Dec 2012

Cited by 26 | Viewed by 8615

Abstract

Liver diseases, such as hepatitis C virus (HCV), are “broken spirit” diseases. The prevalence of HCV infection for American Indian/Alaskan Native (AI/AN) in the United States and Canadian Aboriginals varies; nonetheless, incidence rates of newly diagnosed HCV infection are typically higher relative to [...] Read more.

Liver diseases, such as hepatitis C virus (HCV), are “broken spirit” diseases. The prevalence of HCV infection for American Indian/Alaskan Native (AI/AN) in the United States and Canadian Aboriginals varies; nonetheless, incidence rates of newly diagnosed HCV infection are typically higher relative to non-indigenous people. For AI/AN and Aboriginal peoples risk factors for the diagnosis of HCV can reflect that of the general population: predominately male, a history of injection drug use, in midlife years, with a connection with urban centers. However, the face of the indigenous HCV infected individual is becoming increasingly female and younger compared to non-indigenous counterparts. Epidemiology studies indicate that more effective clearance of acute HCV infection can occur for select Aboriginal populations, a phenomenon which may be linked to unique immune characteristics. For individuals progressing to chronic HCV infection treatment outcomes are comparable to other racial cohorts. Disease progression, however, is propelled by elevated rates of co-morbidities including type 2 diabetes and alcohol use, along with human immunodeficiency virus (HIV) co-infection relative to non-indigenous patients. Historical and personal trauma has a major role in the participation of high risk behaviors and associated diseases. Although emerging treatments provide hope, combating HCV related morbidity and mortality will require interventions that address the etiology of broken spirit diseases. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

601 KiB

Open AccessReview

Pathogenesis of Hepatitis C During Pregnancy and Childhood

by Armelle Le Campion, Ariane Larouche, Sébastien Fauteux-Daniel and Hugo Soudeyns

Viruses 2012, 4(12), 3531-3550; https://doi.org/10.3390/v4123531 - 6 Dec 2012

Cited by 63 | Viewed by 11626

Abstract

The worldwide prevalence of HCV infection is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Yet the pathogenesis of hepatitis C during pregnancy and in the neonatal period remains poorly understood. Mother-to-child transmission (MTCT), a leading cause [...] Read more.

The worldwide prevalence of HCV infection is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Yet the pathogenesis of hepatitis C during pregnancy and in the neonatal period remains poorly understood. Mother-to-child transmission (MTCT), a leading cause of pediatric HCV infection, takes place at a rate of <10%. Factors that increase the risk of MTCT include high maternal HCV viral load and coinfection with HIV-1 but, intriguingly, not breastfeeding and mode of delivery. Pharmacological prevention of MTCT is not possible at the present time because both pegylated interferon alfa and ribavirin are contraindicated for use in pregnancy and during the neonatal period. However, this may change with the recent introduction of direct acting antiviral agents. This review summarizes what is currently known about HCV infection during pregnancy and childhood. Particular emphasis is placed on how pregnancy-associated immune modulation may influence the progression of HCV disease and impact MTCT, and on the differential evolution of perinatally acquired HCV infection in children. Taken together, these developments provide insights into the pathogenesis of hepatitis C and may inform strategies to prevent the transmission of HCV from mother to child. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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351 KiB

Open AccessReview

Host Genetic Variants in the Pathogenesis of Hepatitis C

by Monika Rau, Katharina Baur and Andreas Geier

Viruses 2012, 4(12), 3281-3302; https://doi.org/10.3390/v4123281 - 22 Nov 2012

Cited by 33 | Viewed by 8425

Abstract

Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions [...] Read more.

Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

457 KiB

Open AccessReview

Molecular Signatures of Hepatitis C Virus (HCV)-Induced Type II Mixed Cryoglobulinemia (MCII)

by Giuseppe Sautto, Nicasio Mancini, Massimo Clementi and Roberto Burioni

Viruses 2012, 4(11), 2924-2944; https://doi.org/10.3390/v4112924 - 8 Nov 2012

Cited by 18 | Viewed by 8335

Abstract

The role of hepatitis C virus (HCV) infection in the induction of type II mixed cryoglobulinemia (MCII) and the possible establishment of related lymphoproliferative disorders, such as B-cell non-Hodgkin lymphoma (B-NHL), is well ascertained. However, the molecular pathways involved and the factors predisposing [...] Read more.

The role of hepatitis C virus (HCV) infection in the induction of type II mixed cryoglobulinemia (MCII) and the possible establishment of related lymphoproliferative disorders, such as B-cell non-Hodgkin lymphoma (B-NHL), is well ascertained. However, the molecular pathways involved and the factors predisposing to the development of these HCV-related extrahepatic complications deserve further consideration and clarification. To date, several host- and virus-related factors have been implicated in the progression to MCII, such as the virus-induced expansion of selected subsets of B-cell clones expressing discrete immunoglobulin variable (IgV) gene subfamilies, the involvement of complement factors and the specific role of some HCV proteins. In this review, we will analyze the host and viral factors taking part in the development of MCII in order to give a general outlook of the molecular mechanisms implicated. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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2639 KiB

Open AccessReview

dsRNA-Dependent Protein Kinase PKR and its Role in Stress, Signaling and HCV Infection

by Stéphanie Dabo and Eliane F. Meurs

Viruses 2012, 4(11), 2598-2635; https://doi.org/10.3390/v4112598 - 29 Oct 2012

Cited by 142 | Viewed by 17011

Abstract

The double-stranded RNA-dependent protein kinase PKR plays multiple roles in cells, in response to different stress situations. As a member of the interferon (IFN)‑Stimulated Genes, PKR was initially recognized as an actor in the antiviral action of IFN, due to its ability to [...] Read more.

The double-stranded RNA-dependent protein kinase PKR plays multiple roles in cells, in response to different stress situations. As a member of the interferon (IFN)‑Stimulated Genes, PKR was initially recognized as an actor in the antiviral action of IFN, due to its ability to control translation, through phosphorylation, of the alpha subunit of eukaryotic initiation factor 2 (eIF2a). As such, PKR participates in the generation of stress granules, or autophagy and a number of viruses have designed strategies to inhibit its action. However, PKR deficient mice resist most viral infections, indicating that PKR may play other roles in the cell other than just acting as an antiviral agent. Indeed, PKR regulates several signaling pathways, either as an adapter protein and/or using its kinase activity. Here we review the role of PKR as an eIF2a kinase, its participation in the regulation of the NF-kB, p38MAPK and insulin pathways, and we focus on its role during infection with the hepatitis C virus (HCV). PKR binds the HCV IRES RNA, cooperates with some functions of the HCV core protein and may represent a target for NS5A or E2. Novel data points out for a role of PKR as a pro-HCV agent, both as an adapter protein and as an eIF2a-kinase, and in cooperation with the di-ubiquitin-like protein ISG15. Developing pharmaceutical inhibitors of PKR may help in resolving some viral infections as well as stress-related damages. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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902 KiB

Open AccessReview

Phosphoinositides in the Hepatitis C Virus Life Cycle

by Bryan Bishé, Gulam Syed and Aleem Siddiqui

Viruses 2012, 4(10), 2340-2358; https://doi.org/10.3390/v4102340 - 19 Oct 2012

Cited by 41 | Viewed by 12719

Abstract

Eukaryotes possess seven different phosphoinositides (PIPs) that help form the unique signatures of various intracellular membranes. PIPs serve as docking sites for the recruitment of specific proteins to mediate membrane alterations and integrate various signaling cascades. The spatio-temporal regulation of PI kinases and [...] Read more.

Eukaryotes possess seven different phosphoinositides (PIPs) that help form the unique signatures of various intracellular membranes. PIPs serve as docking sites for the recruitment of specific proteins to mediate membrane alterations and integrate various signaling cascades. The spatio-temporal regulation of PI kinases and phosphatases generates distinct intracellular hubs of PIP signaling. Hepatitis C virus (HCV), like other plus-strand RNA viruses, promotes the rearrangement of intracellular membranes to assemble viral replication complexes. HCV stimulates enrichment of phosphatidylinositol 4-phosphate (PI4P) pools near endoplasmic reticulum (ER) sites by activating PI4KIIIα, the kinase responsible for generation of ER-specific PI4P pools. Inhibition of PI4KIIIα abrogates HCV replication. PI4P, the most abundant phosphoinositide, predominantly localizes to the Golgi and plays central roles in Golgi secretory functions by recruiting effector proteins involved in transport vesicle generation. The PI4P effector proteins also include the lipid-transfer and structural proteins such as ceramide transfer protein (CERT), oxysterol binding protein (OSBP) and Golgi phosphoprotein 3 (GOLPH3) that help maintain Golgi-membrane composition and structure. Depletion of Golgi-specific PI4P pools by silencing PI4KIIIβ, expression of dominant negative CERT and OSBP mutants, or silencing GOLPH3 perturb HCV secretion. In this review we highlight the role of PIPs and specifically PI4P in the HCV life cycle. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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2053 KiB

Open AccessReview

Hepatitis C Virus and Cellular Stress Response: Implications to Molecular Pathogenesis of Liver Diseases

by Po-Yuan Ke and Steve S.-L. Chen

Viruses 2012, 4(10), 2251-2290; https://doi.org/10.3390/v4102251 - 19 Oct 2012

Cited by 64 | Viewed by 20186

Abstract

Infection with hepatitis C virus (HCV) is a leading risk factor for chronic liver disease progression, including steatosis, cirrhosis, and hepatocellular carcinoma. With approximately 3% of the human population infected worldwide, HCV infection remains a global public health challenge. The efficacy of current [...] Read more.

Infection with hepatitis C virus (HCV) is a leading risk factor for chronic liver disease progression, including steatosis, cirrhosis, and hepatocellular carcinoma. With approximately 3% of the human population infected worldwide, HCV infection remains a global public health challenge. The efficacy of current therapy is still limited in many patients infected with HCV, thus a greater understanding of pathogenesis in HCV infection is desperately needed. Emerging lines of evidence indicate that HCV triggers a wide range of cellular stress responses, including cell cycle arrest, apoptosis, endoplasmic reticulum (ER) stress/unfolded protein response (UPR), and autophagy. Also, recent studies suggest that these HCV-induced cellular responses may contribute to chronic liver diseases by modulating cell proliferation, altering lipid metabolism, and potentiating oncogenic pathways. However, the molecular mechanism underlying HCV infection in the pathogenesis of chronic liver diseases still remains to be determined. Here, we review the known stress response activation in HCV infection in vitro and in vivo, and also explore the possible relationship of a variety of cellular responses with the pathogenicity of HCV-associated diseases. Comprehensive knowledge of HCV-mediated disease progression shall shed new insights into the discovery of novel therapeutic targets and the development of new intervention strategy. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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477 KiB

Open AccessReview

RNA Structural Elements of Hepatitis C Virus Controlling Viral RNA Translation and the Implications for Viral Pathogenesis

by David Piñeiro and Encarnación Martinez-Salas

Viruses 2012, 4(10), 2233-2250; https://doi.org/10.3390/v4102233 - 19 Oct 2012

Cited by 33 | Viewed by 8622

Abstract

Hepatitis C virus (HCV) genome multiplication requires the concerted action of the viral RNA, host factors and viral proteins. Recent studies have provided information about the requirement of specific viral RNA motifs that play an active role in the viral life cycle. RNA [...] Read more.

Hepatitis C virus (HCV) genome multiplication requires the concerted action of the viral RNA, host factors and viral proteins. Recent studies have provided information about the requirement of specific viral RNA motifs that play an active role in the viral life cycle. RNA regulatory motifs controlling translation and replication of the viral RNA are mostly found at the 5' and 3' untranslated regions (UTRs). In particular, viral protein synthesis is under the control of the internal ribosome entry site (IRES) element, a complex RNA structure located at the 5'UTR that recruits the ribosomal subunits to the initiator codon. Accordingly, interfering with this RNA structural motif causes the abrogation of the viral cycle. In addition, RNA translation initiation is modulated by cellular factors, including miRNAs and RNA-binding proteins. Interestingly, a RNA structural motif located at the 3'end controls viral replication and establishes long-range RNA-RNA interactions with the 5'UTR, generating functional bridges between both ends on the viral genome. In this article, we review recent advances on virus-host interaction and translation control modulating viral gene expression in infected cells. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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909 KiB

Open AccessReview

Hepatitis C Virus and Natural Compounds: A New Antiviral Approach?

by Noémie Calland, Jean Dubuisson, Yves Rouillé and Karin Séron

Viruses 2012, 4(10), 2197-2217; https://doi.org/10.3390/v4102197 - 17 Oct 2012

Cited by 119 | Viewed by 13457

Abstract

Hepatitis C is a major global health burden with an estimated 160 million infected individuals worldwide. This long-term disease evolves slowly, often leading to chronicity and potentially to liver failure. There is no anti-HCV vaccine, and, until recently, the only treatment available, based [...] Read more.

Hepatitis C is a major global health burden with an estimated 160 million infected individuals worldwide. This long-term disease evolves slowly, often leading to chronicity and potentially to liver failure. There is no anti-HCV vaccine, and, until recently, the only treatment available, based on pegylated interferon and ribavirin, was partially effective, and had considerable side effects. With recent advances in the understanding of the HCV life cycle, the development of promising direct acting antivirals (DAAs) has been achieved. Their use in combination with the current treatment has led to encouraging results for HCV genotype 1 patients. However, this therapy is quite expensive and will probably not be accessible for all patients worldwide. For this reason, constant efforts are being made to identify new antiviral molecules. Recent reports about natural compounds highlight their antiviral activity against HCV. Here, we aim to review the natural molecules that interfere with the HCV life cycle and discuss their potential use in HCV therapy. Full article

(This article belongs to the Special Issue Hepatitis C Pathology)

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