Transient replication of a hepatitis C virus genotype 1b replicon chimera encoding NS5A-5B from genotype 3a

Kylefjord, Helen; Danielsson, Axel; Sedig, Susanne; Belda, Oscar; Wiktelius, Daniel; Vrang, Lotta; Targett-Adams, Paul

doi:10.1016/j.jviromet.2013.09.017

Cited by 3 publications

(3 citation statements)

References 26 publications

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“…Substantial research on new DAAs has been directed toward genotype 1, which is the most prevalent genotype worldwide ( 8 ), with a history of being one of the more difficult genotypes to treat. Today, genotype 3, with high prevalence among PWIDs ( 35 , 36 ), is considered to be the new challenge for effective treatment with many of the recent DAAs ( 12 , 13 , 37 ). Until the latest pan-genotypic DAAs is affordable for the large mass of HCV-patients that needs to be treated, surveillance of genotype prevalence is of importance for national treatment strategies as well as better understanding of treatment of minority genotypes is needed.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of HCV in a Swedish county over 8 years (2002–2009) reveals distinct transmission patterns

Ederth

Jern

Nordér

et al. 2016

Infection Ecology & Epidemiology

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BackgroundHepatitis C virus (HCV) is a major public health concern and data on its molecular epidemiology in Sweden is scarce. We carried out an 8-year population-based study of newly diagnosed HCV cases in one of Sweden's centrally situated counties, Södermanland (D-county). The aim was to characterize the HCV strains circulating, analyze their genetic relatedness to detect networks, and in combination with demographic data learn more about transmission.MethodsMolecular analyses of serum samples from 91% (N=557) of all newly notified cases in D-county, 2002–2009, were performed. Phylogenetic analysis (NS5B gene, 300 bp) was linked to demographic data from the national surveillance database, SmiNet, to characterize D-county transmission clusters. The linear-by-linear association test (LBL) was used to analyze trends over time.ResultsThe most prevalent subtypes were 1a (38%) and 3a (34%). Subtype 1a was most prevalent among cases transmitted via sexual contact, via contaminated blood, or blood products, while subtype 3a was most prevalent among people who inject drugs (PWIDs). Phylogenetic analysis revealed that the subtype 3a sequences formed more and larger transmission clusters (50% of the sequences clustered), while the 1a sequences formed smaller clusters (19% of the sequences clustered), possibly suggesting different epidemics.ConclusionWe found different transmission patterns in D-county which may, from a public health perspective, have implications for how to control virus infections by targeted interventions.

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of HCV in a Swedish county over 8 years (2002–2009) reveals distinct transmission patterns

Ederth

Jern

Nordér

et al. 2016

Infection Ecology & Epidemiology

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“…This replicon chimera represents a useful tool to further study properties/behaviors of polymerase in different HCV genotypes [28]. …”

Section: Ns5b Polymerasementioning

confidence: 99%

“…Recently a replicon-based reagent suitable for convenient investigation of small molecule-mediated inhibition of HCV genotype 3 NS5A and NS5B has been generated and validated. This replicon chimera represents a useful tool to further study properties/behaviors of polymerase in different HCV genotypes [ 28 ].…”

Section: Ns5b Polymerasementioning

confidence: 99%

Updateon different aspects of HCV variability: focus on NS5B polymerase

et al. 2014

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The study of hepatitis C virus (HCV) genotypes/subtypes, quasispecies and recombinants obtained by virus genome sequencing are important for epidemiological studies, to trace the source of infection, for development of new direct acting antivirals (DAAs) therapy and for understanding antiviral selection pressures. The HCV NS5B gene encodes a polymerase, which is responsible for virus replication and is a potential target for the development of antiviral agents. Many studies for classification of HCV use a particular segment of the NS5B gene, in addition to other specific regions, and phylogenetic analysis. Actually, some nucleoside/nucleotide analogues and non-nucleoside inhibitors target NS5B protein. This review focuses on HCV variability, phylogenetic analysis and the role of NS5B in the virus-host interactions.

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Manipulation of both virus- and cell-specific factors is required for robust transient replication of a hepatitis C virus genotype 3a sub-genomic replicon

Kelly

Badhan

Roberts

et al. 2017

Journal of General Virology

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Hepatitis C virus (HCV) genotype (GT) 3 is the second most prevalent of the seven HCV genotypes and exhibits the greatest resistance to the highly potent, direct-acting antivirals (DAAs) that are currently in use. Previously a stable cell line harbouring the S52 GT3 sub-genomic replicon (SGR) was established, but this SGR was unable to robustly replicate transiently. As transient SGRs are a critical tool in the development of DAAs, and in the study of viral resistance, we sought to establish a transient SGR system based on S52. Next-generation sequencing was used to identify putative culture-adaptive substitutions that had arisen during long-term selection of the S52 SGR. A subset of these substitutions was built back into the S52 SGR in the context of a CpG/UpA-low luciferase reporter, with a single point mutation in NS4A conferring the greatest replication capability upon S52. Modification of the innate immune-sensing pathways of Huh7.5 hepatoma cells by expression of the parainfluenza virus type 5 V protein and SEC14L2 resulted in a further enhancement of S52 replication. Furthermore, this transiently replicating SGR showed genotype-specific differences in sensitivity to two clinically relevant NS5A DAAs. In conclusion, we report that a single substitution in NS4A, coupled with host cell modifications, enabled robust levels of transient replication by the GT3 S52 SGR. This system will have beneficial uses in both basic research into the unique aspects of GT3 biology and drug discovery.

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Transient replication of a hepatitis C virus genotype 1b replicon chimera encoding NS5A-5B from genotype 3a

Cited by 3 publications

References 26 publications

Molecular characterization of HCV in a Swedish county over 8 years (2002–2009) reveals distinct transmission patterns

Molecular characterization of HCV in a Swedish county over 8 years (2002–2009) reveals distinct transmission patterns

Updateon different aspects of HCV variability: focus on NS5B polymerase

Manipulation of both virus- and cell-specific factors is required for robust transient replication of a hepatitis C virus genotype 3a sub-genomic replicon

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