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Impact of HCV Diversity in Natural Infection and Models of...
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Impact of HCV Diversity in Natural Infection and Models of Infection

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 10926

Special Issue Editor

Prof. John McLauchlan

E-Mail Website
Guest Editor
MRC-Univeristy of Glasgow Centre for Virus Research, Glasgow G61 1QH, UK
Interests: evolution of hepatitis C virus and dengue virus; emergence and natural occurrence of drug-resistant HCV variants; host reponse to HCV infection

Special Issue Information

Dear Colleagues,

Chronic infection with hepatitis C virus (HCV) is a leading cause of liver disease across the globe and afflicts approximately 71 million individuals. It is estimated that HCV infection is responsible for up to 400,000 deaths annually. At the genetic level, a hallmark of HCV is its extreme diversity. It has been classified into 8 genotypes and 90 subtypes, with an increasing number of additional strains that have yet to be formally classified as subtypes. A consequence of this diversity is that no vaccine is available to protect against infection. However, new therapeutic drugs, called direct-acting antivirals (DAA), are highly successful in curing chronic infection, and indeed, many drug combinations have pan-genotypic activity. In this Special Issue on HCV, the aim will be to provide review articles and original reports describing i) how the diversity of HCV is manifested at the molecular level in terms of its host interactions, ii) the remaining challenges for treating chronic infection with DAA and iii) the approaches that could lead to the development of a vaccine or vaccines for prophylactic use in preventing infection.

Prof. John McLauchlan
Guest Editor

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Keywords

  • hepatitis C virus
  • evolution
  • diversity
  • surveillance
  • response to treatment
  • DAA
  • vaccine
  • immunity
  • virus-host interactions
  • cellular and animal models

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Published Papers (5 papers)

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Research

23 pages, 4287 KiB  
Article
Novel HCV Genotype 4d Infectious Systems and Assessment of Direct-Acting Antivirals and Antibody Neutralization
by Long V. Pham, Rodrigo Velázquez-Moctezuma, Ulrik Fahnøe, Laura Collignon, Priyanka Bajpai, Christina Sølund, Nina Weis, Kenn Holmbeck, Jannick Prentoe and Jens Bukh
Viruses 2022, 14(11), 2527; https://doi.org/10.3390/v14112527 - 15 Nov 2022
Cited by 2 | Viewed by 1864
Abstract
Hepatitis C virus (HCV) genotype 4 is highly prevalent in the Middle East and parts of Africa. Subtype 4d has recently spread among high-risk groups in Europe. However, 4d infectious culture systems are not available, hampering studies of drugs, as well as neutralizing [...] Read more.
Hepatitis C virus (HCV) genotype 4 is highly prevalent in the Middle East and parts of Africa. Subtype 4d has recently spread among high-risk groups in Europe. However, 4d infectious culture systems are not available, hampering studies of drugs, as well as neutralizing antibodies relevant for HCV vaccine development. We determined the consensus 4d sequence from a chronic hepatitis C patient by next-generation sequencing, generated a full-length clone thereof (pDH13), and demonstrated that pDH13 RNA-transcripts were viable in the human-liver chimeric mouse model, but not in Huh7.5 cells. However, a JFH1-based DH13 Core-NS5A 4d clone encoding A1671S, T1785V, and D2411G was viable in Huh7.5 cells, with efficient growth after inclusion of 10 additional substitutions [4d(C5A)-13m]. The efficacies of NS3/4A protease- and NS5A- inhibitors against genotypes 4a and 4d were similar, except for ledipasvir, which is less potent against 4d. Compared to 4a, the 4d(C5A)-13m virus was more sensitive to neutralizing monoclonal antibodies AR3A and AR5A, as well as 4a and 4d patient plasma antibodies. In conclusion, we developed the first genotype 4d infectious culture system enabling DAA efficacy testing and antibody neutralization assessment critical to optimization of DAA treatments in the clinic and for vaccine design to combat the HCV epidemic. Full article
(This article belongs to the Special Issue Impact of HCV Diversity in Natural Infection and Models of Infection)
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11 pages, 1819 KiB  
Article
Characterisation of a Hepatitis C Virus Subtype 2a Cluster in Scottish PWID with a Suboptimal Response to Glecaprevir/Pibrentasvir Treatment
by Rajiv Shah, Stephen T. Barclay, Erica S. Peters, Ray Fox, Rory Gunson, Amanda Bradley-Stewart, Samantha J. Shepherd, Alasdair MacLean, Lily Tong, Vera Jannie Elisabeth van Vliet, Michael Ngan Chiu Bong, Ana Filipe, Emma C. Thomson and Chris Davis
Viruses 2022, 14(8), 1678; https://doi.org/10.3390/v14081678 - 29 Jul 2022
Cited by 2 | Viewed by 2333
Abstract
Direct-acting antivirals (DAAs) have revolutionised the treatment of Hepatitis C virus (HCV), allowing the World Health Organisation (WHO) to set a target of eliminating HCV by 2030. In this study we aimed to investigate glecaprevir and pibrentasvir (GP) treatment outcomes in a cohort [...] Read more.
Direct-acting antivirals (DAAs) have revolutionised the treatment of Hepatitis C virus (HCV), allowing the World Health Organisation (WHO) to set a target of eliminating HCV by 2030. In this study we aimed to investigate glecaprevir and pibrentasvir (GP) treatment outcomes in a cohort of patients with genotype 2a infection. Methods: Clinical data and plasma samples were collected in NHS Greater Glasgow & Clyde. Next generation whole genome sequencing and replicon assays were carried out at the MRC-University of Glasgow Centre for Virus Research. Results: 132 cases infected with genotype 2a HCV were identified. The SVR rate for this group was 91% (112/123) following treatment with GP. An NS5A polymorphism, L31M, was detected in all cases of g2a infection, and L31M+R353K in individuals that failed treatment. The results showed that R353K was present in 90% of individuals in the Glasgow genotype 2a phylogenetic cluster but in less than 5% of all HCV subtype 2a published sequences. In vitro efficacy of pibrentasvir against sub-genomic replicon constructs containing these mutations showed a 2-fold increase in IC50 compared to wildtype. Conclusion: This study describes a cluster of HCV genotype 2a infection associated with a lower-than-expected SVR rate following GP treatment in association with the NS5A mutations L31M+R353K. Full article
(This article belongs to the Special Issue Impact of HCV Diversity in Natural Infection and Models of Infection)
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18 pages, 2442 KiB  
Article
A Human and Rhesus Macaque Interferon-Stimulated Gene Screen Shows That Over-Expression of ARHGEF3/XPLN Inhibits Replication of Hepatitis C Virus and Other Flavivirids
by Connor G. G. Bamford, Elihu Aranday-Cortes, Ricardo Sanchez-Velazquez, Catrina Mullan, Alain Kohl, Arvind H. Patel, Sam J. Wilson and John McLauchlan
Viruses 2022, 14(8), 1655; https://doi.org/10.3390/v14081655 - 28 Jul 2022
Cited by 1 | Viewed by 2231
Abstract
Natural hepatitis C virus (HCV) infection is restricted to humans, whereas other primates such as rhesus macaques are non-permissive for infection. To identify human and rhesus macaque genes that differ or share the ability to inhibit HCV replication, we conducted a medium-throughput screen [...] Read more.
Natural hepatitis C virus (HCV) infection is restricted to humans, whereas other primates such as rhesus macaques are non-permissive for infection. To identify human and rhesus macaque genes that differ or share the ability to inhibit HCV replication, we conducted a medium-throughput screen of lentivirus-expressed host genes that disrupt replication of HCV subgenomic replicon RNA expressing secreted Gaussia luciferase. A combined total of >800 interferon-stimulated genes (ISGs) were screened. Our findings confirmed established anti-HCV ISGs, such as IRF1, PKR and DDX60. Novel species–specific inhibitors were also identified and independently validated. Using a cell-based system that recapitulates productive HCV infection, we identified that over-expression of the ‘Rho Guanine Nucleotide Exchange Factor 3’ gene (ARHGEF3) from both species inhibits full-length virus replication. Additionally, replication of two mosquito-borne flaviviruses, yellow fever virus (YFV) and Zika virus (ZIKV), were also reduced in cell lines over-expressing ARHGEF3 compared to controls. In conclusion, we ascribe novel antiviral activity to the cellular gene ARHGEF3 that inhibits replication of HCV and other important human viral pathogens belonging to the Flaviviridae, and which is conserved between humans and rhesus macaques. Full article
(This article belongs to the Special Issue Impact of HCV Diversity in Natural Infection and Models of Infection)
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15 pages, 3829 KiB  
Article
The Transmission Route and Selection Pressure in HCV Subtype 3a and 3b Chinese Infections: Evolutionary Kinetics and Selective Force Analysis
by Ru Xu, Xia Rong, Elihu Aranday-Cortes, Sreenu Vattipally, Joseph Hughes, John McLauchlan and Yongshui Fu
Viruses 2022, 14(7), 1514; https://doi.org/10.3390/v14071514 - 11 Jul 2022
Cited by 2 | Viewed by 1951
Abstract
Hepatitis C virus (HCV) genotype 3 (GT-3) represents 22–30% of all infections and is the second most common genotype among all HCV genotypes. It has two main subtypes, GT-3a and GT-3b, that present epidemiological differences in transmission groups. This report generated 56 GT-3a [...] Read more.
Hepatitis C virus (HCV) genotype 3 (GT-3) represents 22–30% of all infections and is the second most common genotype among all HCV genotypes. It has two main subtypes, GT-3a and GT-3b, that present epidemiological differences in transmission groups. This report generated 56 GT-3a and 64 GT-3b whole-genome sequences to conduct an evolutionary kinetics and selective force analysis with reference sequences from various countries. Evolutionary analysis showed that HCV GT-3a worldwide might have been transmitted from the Indian subcontinent to South Asia, Europe, North America and then become endemic in China. In China, GT-3a may have been transmitted by intravenous drug users (IDUs) and become endemic in the general population, while GT-3b may have originated from IDUs and then underwent mutual transmission between blood donors (BDs) and IDUs, ultimately becoming independently endemic in IDUs. Furthermore, the spread of GT-3a and GT-3b sequences from BD and IDU populations exhibit different selective pressures: the proportion of positively selected sites (PPSs) in E1 and E2 from IDUs was higher than in BDs. The number of positive selection sites was higher in GT-3b and IDUs. These results indicate that different selective constraints act along with the GT-3a and GT-3b genomes from IDUs and BDs. In addition, GT-3a and GT-3b have different transmission routes in China, which allows us to formulate specific HCV prevention and control strategies in China. Full article
(This article belongs to the Special Issue Impact of HCV Diversity in Natural Infection and Models of Infection)
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15 pages, 610 KiB  
Article
The Neutralizing Antibody Responses of Individuals That Spontaneously Resolve Hepatitis C Virus Infection
by Vanessa M. Cowton, James I. Dunlop, Sarah J. Cole, Rachael E. Swann and Arvind H. Patel
Viruses 2022, 14(7), 1391; https://doi.org/10.3390/v14071391 - 25 Jun 2022
Viewed by 1831
Abstract
Hepatitis C virus (HCV) infection is a major global health problem. In the majority of cases the virus is not cleared by the host immune response and progresses to chronic infection. Studies of the neutralizing antibody responses in individuals that naturally clear infection [...] Read more.
Hepatitis C virus (HCV) infection is a major global health problem. In the majority of cases the virus is not cleared by the host immune response and progresses to chronic infection. Studies of the neutralizing antibody responses in individuals that naturally clear infection are limited. Understanding what constitutes a successful antibody response versus one that has ‘failed’ and resulted in chronic infection is important to understand what type of antibody response would need to be elicited by a protective vaccine. Samples from spontaneous clearers are difficult to obtain therefore studies are often limited. In our study through HCV Research UK, we had access to a cohort of over 200 samples. We identified the samples that contained HCV neutralizing antibodies using ELISA and HCV pseudoparticle (HCVpp) assays. We then utilised mutagenesis and cross-competition analysis to determine the profile of the neutralizing antibody responses. In addition, we analysed a cohort of samples from chronic infection using the same techniques to enable direct comparison of the antibody profiles observed in both cohorts. We conclude that similar profiles are present in both cohorts indicating that it is not the neutralizing antibody response per se that determines the outcome of infection. These data will provide useful information for future HCV vaccine design. Full article
(This article belongs to the Special Issue Impact of HCV Diversity in Natural Infection and Models of Infection)
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