Association of the IFNL4-ΔG Allele With Impaired Spontaneous Clearance of Hepatitis C Virus

Aka, Peter; Kuniholm, Mark H.; Pfeiffer, Ruth M.; Wang, Alan S.; Tang, Wei; Chen, Sabrina; Astemborski, Jacquie; Plankey, Michael; Villacres, Maria C.; Peters, Marion G.; Desai, Seema; Seaberg, Eric C.; Edlin, Brian R.; Strickler, Howard D.; Thomas, David L.; Prokunina‐Olsson, Ludmila; Sharp, Gerald B.; O’Brien, Thomas R.

doi:10.1093/infdis/jit433

Cited by 83 publications

(88 citation statements)

References 10 publications

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“…Roughly, a quarter of HCV-infected individuals clear the virus spontaneously, this largely happens during the acute phase of the infection. Somewhat surprisingly, the genetic variations near the IFNL3 (IL28B) locus are also strongly associated with spontaneous clearance of HCV infection 13,14 . That points towards a pivotal role for IFNls in HCV clearance and a possible influence of IFNls on the adaptive immune response that is generated during the acute phase of HCV infection.…”

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Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

et al. 2014

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Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNl4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNl4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNl4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNl4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.

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confidence: 99%

“…A recent key discovery identified the IFNL4 gene and showed that a polymorphism (rs368234815), which causes the disruption of the IFNL4 reading frame, correlates with a substantially better treatment response 15,16 as well as better spontaneous clearance rate 13 . Thus, patients having a nonfunctional IFNL4 gene are more likely to clear the HCV infection.…”

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Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

et al. 2014

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“…The majority of patients enrolled in the study were African-Americans, who are less likely to have the favorable genotypes CC, TT/TT, and GG at the rs12979860, rs368234815, and rs4803217 loci, respectively. Only 2 of 8 paired biopsies and 4 of 25 unpaired EOT liver biopsies were from patients with the favorable IFNL4 rs368234815-TT/TT genotype, the strongest marker associated with HCV clearance in AfricanAmericans (31,34). Due to high linkage disequilibrium between these markers, the genotypes for the 2 other markers were correlated.…”

Section: Resultsmentioning

confidence: 99%

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

Meissner¹,

Wu²,

Osinusi³

et al. 2014

J. Clin. Invest.

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BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α-based therapies to IFN-α-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia. METHODS.We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed. RESULTS.On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed. CONCLUSION.These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV. TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180. FUNDING. Intramural Programs of the National Institute of Allergy and Infectious The Journal of Clinical Investigation C l i n i C a l M e d i C i n e3 3 5 3 jci.orgVolume 124 Number 8 August 2014We next evaluated on-treatment serum protein levels of select chemokines and cytokines and observed similar expression at baseline and during treatment comparing patients who achieved SVR versus those who relapsed (Supplemental Table 3). Serum levels of the IFN-inducible cytokine IP-10, the protein product of the CXCL10 gene that was downregulated in liver (Figure 2A), correlated significantly with baseline viral load ( Figure 3A). Expression decreased rapidly on-treatment, regardless of treatment outcome, and increased with relapse ( Figure 3B). Viral kinetic and IP-10 decline were significantly correlated ( Figure 3C and Table 1). IL-10 and IFN-γ decreased modestly during treatment, while expression of most other proteins did not change, including TGF-β1 and TIMP1, which are associated with hepatic fibrosis (Supplemental Table 3 and ref. 25).To assess whether a similar pattern of gene expression changes could be observed in the periphery, we performed microarray mRNA analysis in PBMCs collected before treatment, early in treatment (day 6-11), and at EOT (week 24) and identified a significant decrease of IFN signaling during treatment (Supplemental Figure 2 and Supplemental Table 4). qRT-PCR analysis in PBMCs confirmed rapid and sustained downregulation of I...

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“…Bilbert et al reported that induction of IL28B expression is associated with novel TT/ΔG polymorphism ss469415590, which is a better predictor of HCV clearance than rs12979860 [42]. Aka et al studied HIV-positive black women, and found that HCV was cleared in 32.6% of the women with the IFNL4 genotype TT/TT, by comparison with TT/ΔG and G/ΔG genotypes (11.3% and 11.9%, respectively) [43].…”

Section: Ifnl4 and Il28b Polymorphismmentioning

confidence: 99%

IL28B genotyping and treatment of HCV infected subjects

et al. 2014

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Background: Chronic hepatitis C is a common cause of advanced liver disease and appropriate treatment has been complex and a challenge. Reaction of individual genotypes to classical pegylated interferon-ribavirin therapy differs and no success has been achieved in some even after repeated therapy cycles. New types of so called directly acting antivirals (DAAs) are hopeful, as shown in many recent clinical studies, and triple therapy regimens involving DAA are becoming the new standard of care. Objective: To summarize knowledge about the relationship between HCV therapeutic regimens and the genetic background of the host represented by interleukin 28B (IL28B) gene polymorphisms. In the first part, the host basic mechanisms in specific and innate immunity are introduced. The IL28B genotype and its role in the course of HCV treatment are described in the second part. Methods: We searched and summarized publications on HCV therapeutic regimens and host IL28B polymorphisms. Results: Compared to classical regimens, the association between IL28B polymorphism and treatment outcome of HCV infected patients is weaker in triple therapy using first generation DAAs boceprevir and telaprevir. Conclusions:The association between IL28B polymorphism and treatment outcome is lessened with availability of new therapeutic regimens. Nevertheless, IL28B genotyping may still be useful for individualization of treatment strategies.

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Association of the IFNL4-ΔG Allele With Impaired Spontaneous Clearance of Hepatitis C Virus

Cited by 83 publications

References 10 publications

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome

IL28B genotyping and treatment of HCV infected subjects

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