scholarly journals Interferon lambda 4 impacts the genetic diversity of hepatitis C virus

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
M Azim Ansari ◽  
Elihu Aranday-Cortes ◽  
Camilla LC Ip ◽  
Ana da Silva Filipe ◽  
Siu Hin Lau ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Genome ◽  
Association Studies ◽  
Acute Infection ◽  
Adaptive Immune Response ◽  
Spontaneous Clearance ◽  
Genome Wide Association Studies ◽  
Direct Role ◽  
Interferon Lambda

Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.

Serum IFN-λ3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C

2017 ◽  
Vol 35 (6) ◽  
pp. 531-540 ◽  
Author(s):  
Susumu Imoto ◽  
Soo Ryang Kim ◽  
Keisuke Amano ◽  
Etsuko Iio ◽  
Seitetsu Yoon ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Acute Hepatitis ◽  
Association Studies ◽  
Enzyme Linked Immunosorbent Assay ◽  
Spontaneous Clearance ◽  
Acute Hepatitis C ◽  
Genome Wide Association Studies ◽  
Baseline Serum ◽  
Rna Levels

Background: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-λ (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. Aim: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. Materials and Methods: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an in-house, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-α, IFN-β, and IFN-γ induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. Results: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-α and IFN-β were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). Conclusion: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC.

scholarly journals Escape from HLA-B*08-Restricted CD8 T Cells by Hepatitis C Virus Is Associated with Fitness Costs

2008 ◽  
Vol 82 (23) ◽  
pp. 11803-11812 ◽  
Author(s):  
Shadi Salloum ◽  
Cesar Oniangue-Ndza ◽  
Christoph Neumann-Haefelin ◽  
Laura Hudson ◽  
Silvia Giugliano ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Replication ◽  
Consensus Sequence ◽  
Acute Infection ◽  
Spontaneous Clearance ◽  
Fitness Costs ◽  
Genotype 1B ◽  
The Impact

ABSTRACT The inherent sequence diversity of the hepatitis C virus (HCV) represents a major hurdle for the adaptive immune system to control viral replication. Mutational escape within targeted CD8 epitopes during acute HCV infection has been well documented and is one possible mechanism for T-cell failure. HLA-B*08 was recently identified as one HLA class I allele associated with spontaneous clearance of HCV replication. Selection of escape mutations in the immunodominant HLA-B*08-restricted epitope HSKKKCDEL1395-1403 was observed during acute infection. However, little is known about the impact of escape mutations in this epitope on viral replication capacity. Their previously reported reversion back toward the consensus residue in patients who do not possess the B*08 allele suggests that the consensus sequence in this epitope is advantageous for viral replication in the absence of immune pressure. The aim of this study was to determine the impact of mutational escape from this immunodominant epitope on viral replication. We analyzed it with a patient cohort with chronic HCV genotype 1b infection and in a single-source outbreak (genotype 1b). Sequence changes in this highly conserved region are rare and selected almost exclusively in the presence of the HLA-B*08 allele. When tested in the subgenomic replicon (Con1), the observed mutations reduce viral replication compared with the prototype sequence. The results provide direct evidence that escape mutations in this epitope are associated with fitness costs and that the antiviral effect of HLA-B*08-restricted T cells is sufficiently strong to force the virus to adopt a relatively unfavorable sequence.

scholarly journals Interferon lambda 3 genotype predicts hepatitis C virus RNA levels in early acute infection among people who inject drugs: The InC3 Study

2014 ◽  
Vol 61 (3) ◽  
pp. 430-434 ◽  
Author(s):  
Behzad Hajarizadeh ◽  
Bart Grady ◽  
Kimberly Page ◽  
Arthur Y. Kim ◽  
Barbara H. McGovern ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
People Who Inject Drugs ◽  
Acute Infection ◽  
Hepatitis C Virus Rna ◽  
Interferon Lambda ◽  
Virus Rna ◽  
Interferon Lambda 3 ◽  
Rna Levels

scholarly journals The Impact of Interferon Lambda 3 Gene Polymorphism on Natural Course and Treatment of Hepatitis C

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
F. Bellanti ◽  
G. Vendemiale ◽  
E. Altomare ◽  
G. Serviddio
Keyword(s):  
Hepatitis C ◽  
Association Studies ◽  
Acute Infection ◽  
Sustained Viral Response ◽  
Hcv Infection ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Type Iii Ifn ◽  
Chronic Hcv ◽  
The Impact

Host genetic factors may predict the outcome and treatment response in hepatitis C virus (HCV) infection. Very recently, three landmark genome-wide association studies identified single nucleotide polymorphisms near the interleukin 28B (IL28B) region which were more frequent in responders to treatment. IL28B encodes interferon (IFN)λ3, a type III IFN involved in host antiviral immunity. Favourable variants of the two most widely studied IL28B polymorphisms, rs12979860 and rs8099917, are strong pretreatment predictors of early viral clearance and sustained viral response in patients with genotype 1 HCV infection. Further investigations have implicated IL28B in the development of chronic HCV infection versus spontaneous resolution of acute infection and suggest that IL28B may be a key factor involved in host immunity against HCV. This paper presents an overview about the biological activity and clinical applications of IL28B, summarizing the available data on its impact on HCV infection. Moreover, the potential usefulness of IFNλin the treatment and natural history of this disease is also discussed.

Acute infection with a single hepatitis C virus strain in dialysis patients: Analysis of adaptive immune response and viral variability

2009 ◽  
Vol 50 (4) ◽  
pp. 693-704 ◽  
Author(s):  
Lukas Weseslindtner ◽  
Christoph Neumann-Haefelin ◽  
Sergei Viazov ◽  
Anita Haberstroh ◽  
Josef Kletzmayr ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Strain ◽  
Acute Infection ◽  
Adaptive Immune Response ◽  
Dialysis Patients ◽  
Adaptive Immune

scholarly journals Pervasive Adaptation of Hepatitis C Virus to Interferon Lambda Polymorphism Across Multiple Genotypes

2018 ◽  
Author(s):  
Nimisha Chaturvedi ◽  
Evguenia S. Svarovskaia ◽  
Hongmei Mo ◽  
Anu O. Osinusi ◽  
Diana M. Brainard ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Treatment ◽  
Hcv Infection ◽  
Spontaneous Clearance ◽  
Full Cohort ◽  
Interferon Lambda ◽  
Immune Pressure ◽  
A Genome ◽  
Chronic Hcv

Genetic polymorphism in the interferon lambda (IFN-λ) region is associated with spontaneous clearance of hepatitis C virus (HCV) infection and with response to interferon-based antiviral treatment. Here, we evaluate the associations between IFN- λ polymorphism and HCV variation through a genome-to-genome analysis in 8,729 patients from diverse ancestral backgrounds infected with various HCV genotypes. We searched for associations between rs12979860 genotype, a tag for IFN-λ haplotypes, and amino acid variants in the NS3, NS4A, NS5A and NS5B HCV proteins. We report multiple associations between host and pathogen variants in the full cohort as well as in subgroups defined by viral genotype and human ancestry. We also assess the combined impact of human and HCV variation on pre-treatment viral load. By demonstrating that IFN-λ genetic variation leaves a large footprint in the viral genome, this study provides strong evidence of pervasive viral adaptation to host innate immune pressure during chronic HCV infection.

scholarly journals Adaptation of hepatitis C virus to interferon lambda polymorphism across multiple viral genotypes

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Nimisha Chaturvedi ◽  
Evguenia S Svarovskaia ◽  
Hongmei Mo ◽  
Anu O Osinusi ◽  
Diana M Brainard ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hcv Infection ◽  
Spontaneous Clearance ◽  
Interferon Lambda ◽  
Immune Pressure ◽  
Viral Adaptation ◽  
Chronic Hcv Infection ◽  
Chronic Hcv ◽  
Combined Impact

Genetic polymorphism in the interferon lambda (IFN-λ) region is associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to interferon-based treatment. Here, we evaluate associations between IFN-λ polymorphism and HCV variation in 8729 patients (Europeans 77%, Asians 13%, Africans 8%) infected with various viral genotypes, predominantly 1a (41%), 1b (22%) and 3a (21%). We searched for associations between rs12979860 genotype and variants in the NS3, NS4A, NS5A and NS5B HCV proteins. We report multiple associations in all tested proteins, including in the interferon-sensitivity determining region of NS5A. We also assessed the combined impact of human and HCV variation on pretreatment viral load and report amino acids associated with both IFN-λ polymorphism and HCV load across multiple viral genotypes. By demonstrating that IFN-λ variation leaves a large footprint on the viral proteome, we provide evidence of pervasive viral adaptation to innate immune pressure during chronic HCV infection.

scholarly journals Interferon Lambda 4 Genotype Is Associated With Jaundice and Elevated Aminotransferase Levels During Acute Hepatitis C Virus Infection: Findings From the InC3 Collaborative

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Kimberly Page ◽  
Ali Mirzazadeh ◽  
Thomas M. Rice ◽  
Jason Grebely ◽  
Arthur Y. Kim ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Acute Hepatitis ◽  
Spontaneous Clearance ◽  
Acute Hepatitis C ◽  
Hepatitis C Virus Infection ◽  
Symptomatic Disease ◽  
Interferon Lambda ◽  
Using Data

Abstract Symptomatic acute HCV infection and interferon lambda 4 (IFNL4) genotypes are important predictors of spontaneous viral clearance. Using data from a multicohort database (Injecting Cohorts [InC3] Collaborative), we establish an independent association between host IFNL4 genotype and symptoms of acute hepatitis C virus infection. This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease.

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