Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus

Ansari, Azim; Pedergnana, Vincent; Ip, Camilla L. C.; Magrì, Andrea; Delft, Annette von; Bonsall, David; Chaturvedi, Nimisha; Bartha, István; Smith, David A.; Nicholson, George; McVean, Gilean; Trebes, Amy; Piazza, Paolo; Fellay, Jacques; Cooke, Graham; Foster, Graham R.; Hudson, Emma; McLauchlan, John; Simmonds, Peter; Bowden, Rory; Klenerman, Paul; Barnes, Eleanor; Spencer, Chris C. A.

doi:10.1038/ng.3835

Cited by 129 publications

(171 citation statements)

References 65 publications

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“…There is considerable overlap between the ISGs induced in hepatocytes by IFNα and IFNL3 whereas the expression of IFNL4 itself appears to be highly suppressed by the host . As we have recently identified, mutations in the IFNL4 locus are strongly associated with viral adaptations. These mutations are also associated with viral load, and the likely explanation is that they could provide resistance to the impact of endogeneous ISGs, although the exact mechanism requires further exploration.…”

Section: Resultsmentioning

confidence: 87%

“…This study was part of the study described earlier . PAXgene and liver biopsy samples came from patients enrolled in the BOSON study.…”

Section: Methodsmentioning

confidence: 99%

“…SNPs in the IFNL4 region may influence expression, transcription factor binding, or mRNA stability, but overall appear to reduce IFNL3 gene expression . The C allele at SNP rs12979860 tags a dinucleotide insertion polymorphism (rs368234815‐TT) that prevents IFNL4 expression . Using human genotyping arrays combined with whole‐genome viral sequencing, we recently reported viral “footprints” of host IFNL4 genotypes (CC vs. non‐CC at rs12979860).…”

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confidence: 99%

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Impact of Interferon Lambda 4 Genotype on Interferon‐Stimulated Gene Expression During Direct‐Acting Antiviral Therapy for Hepatitis C

Ramamurthy¹,

Marchi²,

Ansari³

et al. 2018

Hepatology

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New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat, including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, patients with cirrhosis receiving a 16‐week course of sofosbuvir and ribavirin had a sustained virological response (SVR) rate of around 50%. In patients with cirrhosis, interferon lambda 4 (IFNL4) CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon‐stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, whereas the reverse was true for non‐CC patients. Conclusion: These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection. (Hepatology 2018; 00:000‐000).

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Section: Resultsmentioning

confidence: 87%

“…This study was part of the study described earlier . PAXgene and liver biopsy samples came from patients enrolled in the BOSON study.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Impact of Interferon Lambda 4 Genotype on Interferon‐Stimulated Gene Expression During Direct‐Acting Antiviral Therapy for Hepatitis C

Ramamurthy¹,

Marchi²,

Ansari³

et al. 2018

Hepatology

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“…Cytokine gene polymorphisms may change the structure and biological function of a certain cytokine coded by the defective gene leading to either increase or decrease of cytokine production. The inheritance of SNP may render people more susceptible or resistant to a certain diseases, therefore affecting cytokine secretion levels, and eventually may influence the outcome of HBV infection [30,31].…”

Section: Discussionmentioning

confidence: 99%

Association of Gene Polymorphisms and Serum Levels of IL-18 with the Susceptibility to Infection with Hepatitis B Virus

Hasan¹,

Naif²

2017

J Infect Dis Med

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Background: IL-18 gene polymorphisms is shown to be involved in various diseases. This study examines the influence of IL-18 gene polymorphism on the natural course of Hepatitis B Virus (HBV) infection together with the impact of serum levels in Iraqi population for the first time.Methods: A total of 55 patients and similar numbers of healthy controls were recruited in this study. Gene polymorphisms at positions -607C/A and -137G/C of IL-18 were examined using the allele-specific polymerase chain reaction (PCR). Serum levels of IL-18 were determined by an ELISA kit.Results: Three genotypes of IL-18-607C/A (rs1946518) were observed and distributed variably in both patients and controls: CC, CA, and AA with frequencies 41 (82%), 3 (6%), and 6 (12%), in patients and in 44 (88%), 5 (10%), and 1 (2%) in the controls, respectively. The homozygous -607AA mutant genotype, A and C allele frequencies were significantly higher (p=0.043) in patients than the healthy control group (A: 15% and 7%, p=0.04 and C: 85% and 93%, p=0.04, respectively) (OR=2.3445, 95%CI=0.9121-6.0269). The effect of treatment against HBV on genotype and allele frequencies compared with untreated patients revealed that CC and AA genotypes were significantly higher (p=0.04) in treated than untreated patients mirrored results obtained in patients and controls. Three genotypes of IL-18-137G/C (rs187238) were observed in both patients and healthy controls: GG, GC, and CC that appeared in 30 (60%), 18 (36%), and 2 (4%) of HBV infected patients and in 32 (64%), 16 (32%), and 2 (4%) of the control group, respectively. No significant genotype or alleles (G and C) frequencies observed between patients and controls (OR=0.863, 95%CI=0.4485-1.7516). Serum levels of IL-18 was found to be significantly higher in HBV-infected patients compared to the control group. IL-18 levels decreased significantly by various genotypes of both SNPs and this was consistently associated with the mutant genotypes of -137 SNP.Conclusion: IL-18-607AA mutant genotype and C and A alleles were significantly associated with a high risk to HBV infection in Iraqi population, however, the -137 genotypes had no clear impact on the disease and its role as a protective factor needs further investigation. In contrast, the downregulation of the circulating levels of IL-18 in patients was associated with the -137 and -607 mutant genotypes.

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“…Although it is obviously necessary to understand all three, we focus on the pathogen (virus) component as this is the most tractable, with the small genomes and rapid replication and evolution of viruses facilitating comparative and experimental studies, and because there is strong evidence for heritable virus genetic variation for virulence 2 . Although we purposely focus on the analysis of virus genomes, genome-wide association studies (GWAS) promise to open up new ways to explore the evolutionary impact of viral infections on host genomes 3 and hence the intimate interaction between host and virus 4 .…”

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confidence: 99%

The phylogenomics of evolving virus virulence

2018

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| How virulence evolves after a virus jumps to a new host species is central to disease emergence. Our current understanding of virulence evolution is based on insights drawn from two perspectives that have developed largely independently: long-standing evolutionary theory based on limited real data examples that often lack a genomic basis, and experimental studies of virulence-determining mutations using cell culture or animal models. A more comprehensive understanding of virulence mutations and their evolution can be achieved by bridging the gap between these two research pathways through the phylogenomic analysis of virus genome sequence data as a guide to experimental study.

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Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus

Cited by 129 publications

References 65 publications

Impact of Interferon Lambda 4 Genotype on Interferon‐Stimulated Gene Expression During Direct‐Acting Antiviral Therapy for Hepatitis C

Impact of Interferon Lambda 4 Genotype on Interferon‐Stimulated Gene Expression During Direct‐Acting Antiviral Therapy for Hepatitis C

Association of Gene Polymorphisms and Serum Levels of IL-18 with the Susceptibility to Infection with Hepatitis B Virus

The phylogenomics of evolving virus virulence

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