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Pathogens
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Hepatitis C Virus: Remaining Challenges
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Hepatitis C Virus: Remaining Challenges

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Viral Pathogens".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 21766

Special Issue Editor

Dr. Che Colpitts

E-Mail Website
Guest Editor
Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
Interests: hepatitis C virus; positive-sense RNA viruses; virus-host interactions; cellular antiviral immunity; viral evasion; antivirals

Special Issue Information

Dear Colleagues,

Since its discovery in 1989, remarkable progress has been made in the understanding of hepatitis C virus (HCV) infection, culminating in the approval of highly effective direct-acting antivirals (DAAs). It has been an outstanding success story. However, DAA access is still limited for the majority of patients, and approximately 70 million people around the world are still chronically infected with HCV and at increased risk for severe liver disease and liver cancer. An effective vaccine will likely be necessary to achieve global elimination of HCV. The development of strategies to mitigate HCV-associated liver disease would also have a major impact on global health. Therefore, despite the tremendous success of DAAs, there are still challenges that remain to be addressed. Moreover, HCV research has contributed greatly to the understanding of fundamental processes in cell biology. The study of HCV virus-host interactions remains highly relevant to dissect fundamental mechanisms of immune evasion and liver disease pathogenesis, and to further understand basic cell biology, including the regulation of lipid membrane homeostasis and the roles of microRNAs in cellular processes.

This Special Issue aims to provide a comprehensive overview of the state-of-the-art of HCV infection, covering a wide range of topics ranging from molecular virology to disease pathogenesis to the latest in HCV treatment and prevention. Submissions in any of these areas are welcomed, including review articles that highlight the achievements and remaining challenges, and research articles focusing on ongoing efforts in the HCV field.

Dr. Che Colpitts
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. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • hepatitis C virus
  • virus-host interactions
  • entry
  • replication
  • assembly
  • lipid membranes
  • adaptive immunity
  • innate immunity
  • viral evasion
  • microRNA
  • vaccine
  • antivirals

Published Papers (7 papers)

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Research

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12 pages, 657 KiB  
Article
High Rates of Hidden HCV Infections among Hospitalized Patients Aged 55–85
by Annarita Valeria Piazzolla, Giulia Paroni, Francesca Bazzocchi, Mauro Cassese, Antonio Cisternino, Luigi Ciuffreda, Franco Gorgoglione, Leonardo Gorgoglione, Vincenzo Palazzo, Natale Sciannamè, Marco Taurchini, Pasquale Vaira, Giovanna Cocomazzi, Maria Maddalena Squillante, Filippo Aucella, Nicola Cascavilla, Salvatore De Cosmo, Michelantonio Fania, Antonio Greco, Antonio Laborante, Maurizio Leone, Evaristo Maiello, Mauro Salvatori, Lazzaro Di Mauro and Alessandra Mangiaadd Show full author list remove Hide full author list
Pathogens 2021, 10(6), 695; https://doi.org/10.3390/pathogens10060695 - 3 Jun 2021
Cited by 6 | Viewed by 2520
Abstract
Background and Aims: The WHO has solicited all countries to eliminate HCV by 2030. The Italian government started routine screening for HCV infection in January 2021, initially targeting subjects born between 1969 and 1989. With the aim of achieving micro-elimination, we designed a [...] Read more.
Background and Aims: The WHO has solicited all countries to eliminate HCV by 2030. The Italian government started routine screening for HCV infection in January 2021, initially targeting subjects born between 1969 and 1989. With the aim of achieving micro-elimination, we designed a hospital-wide project focusing on inpatients born from 1935 to 1985 and conducted it in our institution. Method: All inpatients aged 35 to 85, admitted from 10 February 2020 to 9 February 2021 for many different diseases and conditions underwent HCV antibody (HCVAb) testing by third-generation ELISA. When positive, reflex HCV RNA testing and genotyping were performed. Clinical history, fibrosis diagnosis, laboratory data and concomitant medications were available for all. Results: The HCV screening rate of inpatients was 100%. In total, 11,748 participants were enrolled, of whom 53.50% were male. The HCVAb positivity rate was 3.03%. The HCVAb rate increased with age and was higher for patients born between 1935 and 1944 (4.81%). The rate of HCV RNA positivity was 0.97%. The vast majority (80.70%) of HCV RNA-positive participants were 55 or older; in about 40% of cases, HCV RNA-positive patients were unaware of their infection. Although 16 patients died after HCV chronic infection diagnosis (two due COVID-19) or HCV treatment prescription (one due to COVID-19), 74.56% of patient HCV diagnoses were linked to HCV treatment, despite their co-morbidities. All patients older than 65 who died had an active HCV infection. Conclusion: The present study revealed a rate of active HCV infections among inpatients lower than what has been reported in the past in the general population; this appears to be a result of the widespread use of pangenotypic direct-acting antiviral agents (DAAs). The overall rate of active infection was lower than the rate observed in the 1935–1954 cohort. The high rate of inpatients unaware of HCV infections and the high number of deaths among subjects with an active HCV infection born from 1935 to 1954, suggest that, at least in southern Italy, targeted screening of this birth cohort may be required to reduce the number of undiagnosed cases and hidden infections. Full article
(This article belongs to the Special Issue Hepatitis C Virus: Remaining Challenges)
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15 pages, 4365 KiB  
Article
Comparative Analysis of Hepatitis C Virus NS5A Dynamics and Localization in Assembly-Deficient Mutants
by Laura Riva, Corentin Spriet, Nicolas Barois, Costin-Ioan Popescu, Jean Dubuisson and Yves Rouillé
Pathogens 2021, 10(2), 172; https://doi.org/10.3390/pathogens10020172 - 4 Feb 2021
Cited by 2 | Viewed by 2058
Abstract
The hepatitis C virus (HCV) life cycle is a tightly regulated process, during which structural and non-structural proteins cooperate. However, the interplay between HCV proteins during genomic RNA replication and progeny virion assembly is not completely understood. Here, we studied the dynamics and [...] Read more.
The hepatitis C virus (HCV) life cycle is a tightly regulated process, during which structural and non-structural proteins cooperate. However, the interplay between HCV proteins during genomic RNA replication and progeny virion assembly is not completely understood. Here, we studied the dynamics and intracellular localization of non-structural 5A protein (NS5A), which is a protein involved both in genome replication and encapsidation. An NS5A-eGFP (enhanced green fluorescent protein) tagged version of the strain JFH-1-derived wild-type HCV was compared to the corresponding assembly-deficient viruses Δcore, NS5A basic cluster 352–533 mutant (BCM), and serine cluster 451 + 454 + 457 mutant (SC). These analyses highlighted an increase of NS5A motility when the viral protein core was lacking. Although to a lesser extent, NS5A motility was also increased in the BCM virus, which is characterized by a lack of interaction of NS5A with the viral RNA, impairing HCV genome encapsidation. This observation suggests that the more static NS5A population is mainly involved in viral assembly rather than in RNA replication. Finally, NS4B exhibited a reduced co-localization with NS5A and lipid droplets for both Δcore and SC mutants, which is characterized by the absence of interaction of NS5A with core. This observation strongly suggests that NS5A is involved in targeting NS4B to lipid droplets (LDs). In summary, this work contributes to a better understanding of the interplay between HCV proteins during the viral life cycle. Full article
(This article belongs to the Special Issue Hepatitis C Virus: Remaining Challenges)
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Review

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19 pages, 1877 KiB  
Review
MicroRNA-122 Regulation of HCV Infections: Insights from Studies of miR-122-Independent Replication
by Mamata Panigrahi, Michael A. Palmer and Joyce A. Wilson
Pathogens 2022, 11(9), 1005; https://doi.org/10.3390/pathogens11091005 - 2 Sep 2022
Cited by 6 | Viewed by 2154
Abstract
Despite the advancement in antiviral therapy, Hepatitis C remains a global health challenge and one of the leading causes of hepatitis related deaths worldwide. Hepatitis C virus, the causative agent, is a positive strand RNA virus that requires a liver specific microRNA called [...] Read more.
Despite the advancement in antiviral therapy, Hepatitis C remains a global health challenge and one of the leading causes of hepatitis related deaths worldwide. Hepatitis C virus, the causative agent, is a positive strand RNA virus that requires a liver specific microRNA called miR-122 for its replication. Unconventional to the canonical role of miRNAs in translation suppression by binding to 3′Untranslated Region (UTR) of messenger RNAs, miR-122 binds to two sites on the 5′UTR of viral genome and promotes viral propagation. In this review, we describe the unique relationship between the liver specific microRNA and HCV, the current knowledge on the mechanisms by which the virus uses miR-122 to promote the virus life cycle, and how miR-122 impacts viral tropism and pathogenesis. We will also discuss the use of anti-miR-122 therapy and its impact on viral evolution of miR-122-independent replication. This review further provides insight into how viruses manipulate host factors at the initial stage of infection to establish a successful infection. Full article
(This article belongs to the Special Issue Hepatitis C Virus: Remaining Challenges)
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12 pages, 596 KiB  
Review
Uncovering Resistance to Hepatitis C Virus Infection: Scientific Contributions and Unanswered Questions in the Irish Anti-D Cohort
by Jamie A. Sugrue and Cliona O’Farrelly
Pathogens 2022, 11(3), 306; https://doi.org/10.3390/pathogens11030306 - 28 Feb 2022
Cited by 1 | Viewed by 2298
Abstract
Infections caused inadvertently during clinical intervention provide valuable insight into the spectrum of human responses to viruses. Delivery of hepatitis C virus (HCV)-contaminated blood products in the 70s (before HCV was identified) have dramatically increased our understanding of the natural history of HCV [...] Read more.
Infections caused inadvertently during clinical intervention provide valuable insight into the spectrum of human responses to viruses. Delivery of hepatitis C virus (HCV)-contaminated blood products in the 70s (before HCV was identified) have dramatically increased our understanding of the natural history of HCV infection and the role that host immunity plays in the outcome to viral infection. In Ireland, HCV-contaminated anti-D immunoglobulin (Ig) preparations were administered to approximately 1700 pregnant Irish rhesus-negative women in 1977–1979. Though tragic in nature, this outbreak (alongside a smaller episode in 1993) has provided unique insight into the host factors that influence outcomes after HCV exposure and the subsequent development of disease in an otherwise healthy female population. Despite exposure to highly infectious batches of anti-D, almost 600 of the HCV-exposed women have never shown any evidence of infection (remaining negative for both viral RNA and anti-HCV antibodies). Detailed analysis of these individuals may shed light on innate immune pathways that effectively block HCV infection and potentially inform us more generally about the mechanisms that contribute to viral resistance in human populations. Full article
(This article belongs to the Special Issue Hepatitis C Virus: Remaining Challenges)
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15 pages, 1884 KiB  
Review
Cyclophilins and Their Roles in Hepatitis C Virus and Flavivirus Infections: Perspectives for Novel Antiviral Approaches
by Carla E. Gallardo-Flores and Che C. Colpitts
Pathogens 2021, 10(7), 902; https://doi.org/10.3390/pathogens10070902 - 17 Jul 2021
Cited by 4 | Viewed by 4693
Abstract
Cyclophilins are cellular peptidyl-prolyl isomerases that play an important role in viral infections, with demonstrated roles in the replication of hepatitis C virus (HCV) and other viruses in the Flaviviridae family, such as dengue virus (DENV) and yellow fever virus (YFV). Here, we [...] Read more.
Cyclophilins are cellular peptidyl-prolyl isomerases that play an important role in viral infections, with demonstrated roles in the replication of hepatitis C virus (HCV) and other viruses in the Flaviviridae family, such as dengue virus (DENV) and yellow fever virus (YFV). Here, we discuss the roles of cyclophilins in HCV infection and provide a comprehensive overview of the mechanisms underlying the requirement for cyclophilins during HCV replication. Notably, cyclophilin inhibitor therapy has been demonstrated to be effective in reducing HCV replication in chronically infected patients. While the roles of cyclophilins are relatively well-understood for HCV infection, cyclophilins are more recently emerging as host factors for flavivirus infection as well, providing potential new therapeutic avenues for these viral infections which currently lack antiviral therapies. However, further studies are required to elucidate the roles of cyclophilins in flavivirus replication. Here, we review the current knowledge of the role of cyclophilins in HCV infection to provide a conceptual framework to understand how cyclophilins may contribute to other viral infections, such as DENV and YFV. Improved understanding of the roles of cyclophilins in viral infection may open perspectives for the development of cyclophilin inhibitors as effective antiviral therapeutics for HCV and related viruses. Full article
(This article belongs to the Special Issue Hepatitis C Virus: Remaining Challenges)
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19 pages, 2157 KiB  
Review
Hepatitis C Virus Glycan-Dependent Interactions and the Potential for Novel Preventative Strategies
by Emmanuelle V. LeBlanc, Youjin Kim, Chantelle J. Capicciotti and Che C. Colpitts
Pathogens 2021, 10(6), 685; https://doi.org/10.3390/pathogens10060685 - 1 Jun 2021
Cited by 8 | Viewed by 4351
Abstract
Chronic hepatitis C virus (HCV) infections continue to be a major contributor to liver disease worldwide. HCV treatment has become highly effective, yet there are still no vaccines or prophylactic strategies available to prevent infection and allow effective management of the global HCV [...] Read more.
Chronic hepatitis C virus (HCV) infections continue to be a major contributor to liver disease worldwide. HCV treatment has become highly effective, yet there are still no vaccines or prophylactic strategies available to prevent infection and allow effective management of the global HCV burden. Glycan-dependent interactions are crucial to many aspects of the highly complex HCV entry process, and also modulate immune evasion. This review provides an overview of the roles of viral and cellular glycans in HCV infection and highlights glycan-focused advances in the development of entry inhibitors and vaccines to effectively prevent HCV infection. Full article
(This article belongs to the Special Issue Hepatitis C Virus: Remaining Challenges)
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11 pages, 728 KiB  
Review
Liver Abnormalities after Elimination of HCV Infection: Persistent Epigenetic and Immunological Perturbations Post-Cure
by Stephen J. Polyak, I. Nicholas Crispe and Thomas F. Baumert
Pathogens 2021, 10(1), 44; https://doi.org/10.3390/pathogens10010044 - 7 Jan 2021
Cited by 13 | Viewed by 2658
Abstract
Chronic hepatitis C (CHC) is a major cause of hepatocellular carcinoma (HCC) worldwide. While directly acting antiviral (DAA) drugs are now able to cure virtually all hepatitis C virus (HCV) infections, even in subjects with advanced liver disease, what happens to the liver [...] Read more.
Chronic hepatitis C (CHC) is a major cause of hepatocellular carcinoma (HCC) worldwide. While directly acting antiviral (DAA) drugs are now able to cure virtually all hepatitis C virus (HCV) infections, even in subjects with advanced liver disease, what happens to the liver and progression of the disease after DAA-induced cure of viremia is only beginning to emerge. Several large-scale clinical studies in different patient populations have shown that patients with advanced liver disease maintain a risk for developing HCC even when the original instigator, the virus, is eliminated by DAAs. Here we review emerging studies derived from multiple, complementary experimental systems involving patient liver tissues, human liver cell cultures, human liver slice cultures, and animal models, showing that HCV infection induces epigenetic, signaling, and gene expression changes in the liver associated with altered hepatic innate immunity and liver cancer risk. Of critical importance is the fact that these virus-induced abnormalities persist after DAA cure of HCV. These nascent findings portend the discovery of pathways involved in post-HCV immunopathogenesis, which may be clinically actionable targets for more comprehensive care of DAA-cured individuals. Full article
(This article belongs to the Special Issue Hepatitis C Virus: Remaining Challenges)
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