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Impact of virus subtype and host IFNL4 genotype on large-scale RNA structure formation in the genome of hepatitis C virus.

ABSTRACT: Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute previously associated with formation of large-scale RNA structure in their genomic RNA. We developed novel methods to analyze and visualize genome-scale ordered RNA structure (GORS) predicted from the increasingly large data sets of complete genome sequences of HCV. Structurally conserved RNA secondary structure in coding regions of HCV localized exclusively to polyprotein ends (core, NS5B). Coding regions elsewhere were also intensely structured based on elevated minimum folding energy difference (MFED) values, but the actual stem-loop elements involved in genome folding were structurally poorly conserved, even between subtypes 1a and 1b. Dynamic remodeling was further evident from comparison of HCV strains in different host genetic backgrounds. Significantly higher MFED values, greater suppression of UpA dinucleotide frequencies, and restricted diversification were found in subjects with the TT genotype of the rs12979860 SNP in the IFNL4 gene compared to the CC (nonexpressing) allele. These structural and compositional associations with expression of interferon-?4 were recapitulated on a larger scale by higher MFED values and greater UpA suppression of genotype 1 compared to genotype 3a, associated with previously reported HCV genotype-associated differences in hepatic interferon-stimulated gene induction. Associations between innate cellular responses with HCV structure and further evolutionary constraints represent an important new element in RNA virus evolution and the adaptive interplay between virus and host.

SUBMITTER: Simmonds P

PROVIDER: S-EPMC7566573 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Impact of virus subtype and host <i>IFNL4</i> genotype on large-scale RNA structure formation in the genome of hepatitis C virus.

Simmonds Peter P Cuypers Lize L Irving Will L WL McLauchlan John J Cooke Graham S GS Barnes Ellie E Ansari M Azim MA

RNA (New York, N.Y.) 20200803 11

Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute previously associated with formation of large-scale RNA structure in their genomic RNA. We developed novel methods to analyze and visualize genome-scale ordered RNA structure (GORS) predicted from ...[more]

PMID: 32747607

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Project description:BackgroundHepatitis C virus (HCV) is one of the leading causes of chronic liver disease. Seven genotypes and more than 80 subtypes have been identified for HCV so far. To date, 10 subtypes (3a to 3i; and 3k) of HCV genotype 3 have been identified. In 2006, two HCV isolates were reported from Iran that belonged to a new subtype of genotype 3. However, considering the consensus proposal for HCV genotype nomenclature, the available sequences of the new subtype did not correspond to the regions that are required to be analyzed prior to subtype assignment. During a study on the molecular epidemiology of HCV in Iran, an HCV isolate (FSM165) which seemed to belong to a new subtype of genotype 3 was obtained from a patient residing in Tehran, Iran.ObjectivesThe aim of this study was to assess the relatedness of isolate FM165 together with several sequences retrieved from the database to the new HCV-3 subtype reported from Iran in 2006.Materials and methodsVarious parts of the genome including the core/E1 region and two segments of the NS5B region were amplified and sequenced for isolate FSM165. Furthermore, using the Basic Local Alignment Search Tool (BLAST), the HCV database was searched for sequences that had a high level of similarity with sequences of FSM165 isolate and such sequences were retrieved from the database. To investigate the relatedness of isolate FSM165 and also the retrieved sequences to a new HCV-3 subtype reported previously, phylogenetic analyses were performed using the Kimura two-parameter model and the neighbor joining method.ResultsPhylogenetic analysis of the partial NS5B region demonstrated the relatedness of isolate FSM165 to the new subtype reported from Iran in 2006. Moreover, some core/E1 and NS5B sequences that had a high level of similarity with FSM165 isolate were found through searching the HCV database. These sequences were previously either misclassified or could not be accurately classified. Phylogenetic analyses showed that all of the described sequences belonged to the new subtype of HCV genotype 3.ConclusionsData suggests that the new subtype has a vast geographical distribution in Iran. The core/E1 and the NS5B sequences described in this paper can be used as references for the new HCV-3 subtype in future studies.

Project description:BackgroundSix distinct genetic variants (genotypes 1 - 6) of hepatitis C virus (HCV) exist globally. Certain genotypes are more prevalent in particular countries or regions than in others but, globally, genotype 3 (GT3) is the second most common. Patients infected with HCV GT1, 2, 4, 5 or 6 recover to a greater extent, as measured by sustained virological response (SVR), following treatment with regimens based on direct-acting antivirals (DAAs) than after treatment with older regimens based on pegylated interferon (Peg-IFN). GT3, however, is regarded as being more difficult to treat as it is a relatively aggressive genotype, associated with greater liver damage and cancer risk; some subgroups of patients with GT3 infection are less responsive to current licensed DAA treatments. Newer DAAs have become available or are in development.MethodsAccording to PRISMA guidance, we conducted a systematic review (and descriptive statistical analysis) of data in the public domain from relevant clinical trial or observational (real-world) study publications within a 5-year period (February 2011 to May 2016) identified by PubMed, Medline In-Process, and Embase searches. This was supplemented with a search of five non-indexed literature sources, comprising annual conferences of the AASLD, APASL, CROI, EASL, and WHO, restricted to a 1-year period (April 2015 to May 2016).ResultsOf the all-oral regimens, the efficacy (SVR12 ≥ 90%) of sofosbuvir plus daclatasvir- and velpatasvir-based regimens in clinical trials supports and reinforces their recommendation by guidelines. Other promising regimens comprise grazoprevir + elbasvir + sofosbuvir, and ombitasvir + paritaprevir/ribavirin + sofosbuvir. Newer regimens incorporating pibrentasvir + glecaprevir or grazoprevir + ruzasvir + MK-3682 (uprifosbuvir), offer all-oral, ribavirin-free SVR12 rates consistently greater than 95%. Observational studies report slightly lower overall SVR rates but reflect corresponding clinical trial data in terms of treatments most likely to achieve good responses.ConclusionsOn the basis of SVR12, we established that for treating GT3 infections (i) regimens incorporating newer DAAs are more effective than those comprising older DAAs, and (ii) ribavirin may be of less benefit in newer DAA regimens than in older DAA regimens. The analysis provides evidence that DAA regimens can replace Peg-IFN-based regimens for GT3 infection.

Dataset Information

Impact of virus subtype and host IFNL4 genotype on large-scale RNA structure formation in the genome of hepatitis C virus.

Publications

Impact of virus subtype and host <i>IFNL4</i> genotype on large-scale RNA structure formation in the genome of hepatitis C virus.

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