Interferon-λ Genetic Variations and Hepatitis C: Yet to be Discovered.
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ABSTRACT:
SUBMITTER: Keshvari M
PROVIDER: S-EPMC4071313 | biostudies-literature | 2014 May
REPOSITORIES: biostudies-literature
Publications
Interferon-λ Genetic Variations and Hepatitis C: Yet to be Discovered.
Keshvari Maryam M Sharafi Heidar H
Hepatitis monthly 20140510 5
Similar Datasets
Project description: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.
| S-EPMC6721795 | biostudies-literature
Project description:AimTo evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-λ (IFNL) polymorphisms.MethodsThis study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type of pegylated interferon. Patients were treated with 180 μg pegylated interferon alpha-2a (Pegaferon(®)) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus (HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes.ResultsA total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men (92.8%). The most frequent HCV genotype was type-1, infecting 93/152 (61.2%) patients. Sustained virologic response (SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2% (52/57) of patients with the IFNL rs12979860 CC genotype and 82.1% (78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT (39/45; 86.7%) and non-TT (61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR (OR = 6.2; 95%CI: 1.2-31.9; P = 0.03).ConclusionThe rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.
| S-EPMC4528037 | biostudies-literature
Project description:Interferon (IFN)-α, a type-I IFN, is widely used to treat chronic hepatitis C virus infection, but the broad expression of IFN-α receptors often leads to adverse reactions in many organs. Here, we examine IFN-λ, a type-III IFN, as a therapeutic alternative to IFN-α. Like IFN-α, IFN-λ also induces antiviral activity in hepatocytes, but might induce fewer adverse reactions because its receptor is largely restricted to cells of epithelial origin. We also discuss the recent discovery of single nucleotide polymorphisms (SNPs) near the human IFN-λ3 gene, IL28B, that correlate strongly with the ability to achieve a sustained virological response to therapy with pegylated IFN-α plus ribavirin in patients with chronic hepatitis C.
| S-EPMC3163738 | biostudies-literature
Project description:Interferon (IFN)-α, a type-I IFN, is widely used to treat chronic hepatitis C virus infection, but the broad expression of IFN-α receptors often leads to adverse reactions in many organs. Here, we examine IFN-λ, a type-III IFN, as a therapeutic alternative to IFN-α. Like IFN-α, IFN-λ also induces antiviral activity in hepatocytes, but might induce fewer adverse reactions because its receptor is largely restricted to cells of epithelial origin. We also discuss the recent discovery of single nucleotide polymorphisms (SNPs) near the human IFN-λ3 gene, IL28B, that correlate strongly with the ability to achieve a sustained virological response to therapy with pegylated IFN-α plus ribavirin in patients with chronic hepatitis C.
| S-EPMC3163738 | biostudies-literature
Project description:UnlabelledHepatitis C virus (HCV) replication in primary liver cells is less robust than that in hepatoma cell lines, suggesting that innate antiviral mechanisms in primary cells may limit HCV replication or spread. Here we analyzed the expression of 47 genes associated with interferon (IFN) induction and signaling following HCV infection of primary human fetal liver cell (HFLC) cultures from 18 different donors. We report that cell culture-produced HCV (HCVcc) induced expression of Type III (λ) IFNs and of IFN-stimulated genes (ISGs). Little expression of Type I IFNs was detected. Levels of IFNλ and ISG induction varied among donors and, often, between adapted and nonadapted HCV chimeric constructs. Higher levels of viral replication were associated with greater induction of ISGs and of λ IFNs. Gene induction was dependent on HCV replication, as ultraviolet light-inactivated virus was not stimulatory and an antiviral drug, 2'-C-methyladenosine, reduced induction of λ IFNs and ISGs. The level of IFNλ protein induced was sufficient to inhibit HCVcc infection of naïve cultures.ConclusionTogether, these results indicate that despite its reported abilities to blunt the induction of an IFN response, HCV infection is capable of inducing antiviral cytokines and pathways in primary liver cell cultures. Induction of ISGs and λ IFNs may limit the growth and spread of HCV in primary cell cultures and in the infected liver. HCV infection of HFLC may provide a useful model for the study of gene induction by HCV in vivo.
| S-EPMC3219820 | biostudies-literature
Project description:ContextPolymorphisms of the interferon lambda 3 (IFNL3) gene have been proposed to be associated with drug-induced clearance of the hepatitis C virus (HCV). However, the role of IFNL3 polymorphisms in the prediction of treatment on chronic hepatitis B (CHB) patients have yielded controversial results. The aim of this study was to clarify the role of IFNL3 polymorphisms (rs12979860, rs8099917, and rs12980275) in the treatment response of CHB patients to interferon (IFN).Evidence acquisitionEMBASE and PUBMED/MEDLINE were searched to identify relevant studies from January 2009 to March 2015. The search used the keyword "interferon lambda 3" or "IFNL3," combined with the following terms: "interferon therapy," "hepatitis," and "polymorphisms." Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were used to assess the strength of the associations between the polymorphisms and the response to IFN therapy.ResultsNine studies of 1602 CHB patients receiving IFN treatment were included. Under the random-effects model, patients expressing the variant rs12980275 showed a significantly increased response to IFN therapy (OR = 2.85; 95% CI = 1.14 - 4.60). In the subgroup analyses by antiviral agents, the patients carrying the rs8099917T allele in the IFN-only treatment group showed a significantly increased response to IFN therapy (OR for the dominant model = 2.03; 95% CI = 1.24 - 3.31), whereas those in the mixed treatment group showed a significantly decreased response (OR for the dominant model = 0.30; 95% CI = 0.10 - 0.90).ConclusionsThis study supports the idea that the IFNL3 gene is an important predictor of the response of CHB patients to IFN therapy.
| S-EPMC5026730 | biostudies-literature
Project description:AimTo determine the association between rapid viral response and IL28B, IL28RA, IL10RB and MxA polymorphisms in the Chinese Han population.MethodsThe study cohort consisted of 238 chronic hepatitis C patients treated with interferon (IFN)-α-2b and ribavirin. Six single nucleotide polymorphisms were genotyped using the ABI TaqMan allelic discrimination assay. Biochemical indices were measured at baseline. Serum hepatitis C virus (HCV) RNA was detected at weeks 0, 4, 12 and 24 of therapy.ResultsOnly IL28B rs12980275 was associated with treatment response in the Chinese Han population. Patients carrying AG/GG genotypes had a reduced rapid viral response compared with patients carrying the AA genotype (additive model: adjusted OR = 0.43, 95%CI: 0.24-0.75). It took less time for patients with the AA genotype to achieve a viral load < 500 copies/mL (log-rank test, P = 0.004). In addition, the protective effect of genotype AA was independent of baseline viral load. HCV genotype, and baseline white blood cell count, α-fetoprotein and viral load might also help predict treatment response. The area under the receiver-operating characteristic curve was 0.726.ConclusionIL28B rs12980275 AA genotype is a strong predictor of positive response to IFN therapy in Chinese Han patients with hepatitis C.
| S-EPMC4385550 | biostudies-literature
Project description: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.
| S-EPMC6721370 | biostudies-literature
Project description:Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHHs) approaching single-cell resolution. An innate antiviral immune signature dominated the transcriptional response but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection.
| S-EPMC4104123 | biostudies-literature
Project description:Hepatitis C virus (HCV) infection can result in viral chronicity or clearance. Although host genetics and particularly genetic variation in the interferon lambda (IFNL) locus are associated with spontaneous HCV clearance and treatment success, the mechanisms guiding these clinical outcomes remain unknown. Using a laser capture microdissection-driven unbiased systems virology approach, we isolated and transcriptionally profiled HCV-infected and adjacent primary human hepatocytes (PHH) approaching single cell resolution. An innate antiviral immune signature dominated the transcriptional response, but differed in magnitude and diversity between HCV-infected and adjacent cells. Molecular signatures associated with more effective antiviral control were determined by comparing donors with high and low infection frequencies. Cells from donors with clinically unfavorable IFNL genotypes were infected at a greater frequency and exhibited dampened antiviral and cell death responses. These data suggest that early virus-host interactions, particularly host genetics and induction of innate immunity, critically determine the outcome of HCV infection. Cell populations of primary human hepatocytes were collected via laser capture microdissection, their transcriptomes were amplified and analyzed via whole Illumina genome microarray. Three populations were collected: virus infected cells, cells adjacent to infected cells (“adjacent”) and mock infected cells. Cells from multiple donors were employed to address host genetic variability on our observed phenotypes. Nine different donors were assessed on 1-day post infection and three donors were assessed 3 days post infection and and four donors were assessed on 7 days post infection. For each cell population (virus infected, adjacent or mock), four biological replicate arrays were performed. In total, we analyzed 186 microarrays
2014-02-12 | E-GEOD-54648 | biostudies-arrayexpress