The IFNL3/4 ΔG variant increases susceptibility to cytomegalovirus retinitis among HIV-infected patients

Bibert, Stéphanie; Wójtowicz, Agnieszka; Taffé, Patrick; Manuel, Oriol; Bernasconi, Enos; Furrer, Hansjakob; Günthard, Huldrych F.; Hoffmann, Matthias; Kaiser, Laurent; Osthoff, Michael; Cavassini, Matthias; Bochud, Pierre–Yves

doi:10.1097/qad.0000000000000379

Cited by 41 publications

(37 citation statements)

References 18 publications

(25 reference statements)

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“…These observations point towards a fundamental role of active IFNl4 in facilitating and maintaining a chronic HCV infection. A recent study showed that rs368234815 also influenced susceptibility to cytomegalovirus retinitis among HIV-infected patients 31 , suggesting that the IFNl4 protein might play detrimental role in several different chronic viral infections. Thus, we believe that the activity of IFNl4 could play an important role in multiple chronic viral infections by a mechanism similar to that observed in hepatitis C.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…The malicious effect of IFNλ4 might extend to other chronic viral infections, as recent data suggest for cytomegalovirus infection. 21,22 The paradoxical situation that an apparent antiviral cytokine is disadvantageous during viral infection, and the current inability to explain why this effect is specific to IFNλ4, has spurred speculation toward alternative signaling pathways of IFNλ4. 23 In order to determine whether IFNλ4 can induce an alternative set of genes, that are not induced in the classical IFN response, we have compared the transcriptional response after IFNα, IFNλ3 and IFNλ4 stimulation in both primary human hepatocytes (PHH) and primary human airway epithelial (HAE) cells using transcriptome sequencing (RNA-seq).…”

Section: Introductionmentioning

confidence: 98%

Transcriptome analysis reveals a classical interferon signature induced by IFNλ4 in human primary cells

et al. 2015

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The IFNL4 gene is negatively associated with spontaneous and treatment-induced clearance of hepatitis C virus infection. The activity of IFNλ4 has an important causal role in the pathogenesis, but the molecular details are not fully understood. One possible reason for the detrimental effect of IFNλ4 could be a tissue-specific regulation of an unknown subset of genes. To address both tissue and subtype specificity in the interferon response, we treated primary human hepatocytes and airway epithelial cells with IFNα, IFNλ3 or IFNλ4 and assessed interferon mediated gene regulation using transcriptome sequencing. Our data show a surprisingly similar response to all three subtypes of interferon. We also addressed the tissue specificity of the response, and identified a subset of tissue-specific genes. However, the interferon response is robust in both tissues with the majority of the identified genes being regulated in hepatocytes as well as airway epithelial cells. Thus we provide an in-depth analysis of the liver interferon response seen over an array of interferon subtypes and compare it to the response in the lung epithelium.

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“…60,61,[65][66][67][68][69][70] In particular, SNPs in IFNL3 (rs8099917) and IFNL4 (rs368234815) have been proposed as predictors for spontaneous viral clearance and treatment success to pegylated interferon a/ribavirin (PEG-IFN-a/RBV) treatment. 60,61 The IFNL4 SNP (rs368234815) has also been associated with CMV retinitis in HIV-infected risk patients (nD1134, p-valueD7E-3), 71 as well as with CMV replication in solid-organ transplant recipients at risk (nD455, p-valueD4E-02). 72 Moreover, an IFNL3 SNP (rs8099917) may modulate the humoral immune response after vaccination.…”

Section: Impact Of Snps On the Humoral Immune Responsementioning

confidence: 99%

Impact of host genetic polymorphisms on vaccine induced antibody response

Linnik¹,

Egli

2016

Human Vaccines & Immunotherapeutics

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The IFNL3/4 ΔG variant increases susceptibility to cytomegalovirus retinitis among HIV-infected patients

Abstract: We reported for the first time an association between an IFNL3/4 polymorphism and susceptibility to AIDS-related CMV retinitis. IFNL3/4 may influence immunity against viruses other than HCV.

Cited by 41 publications

References 18 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

Transcriptome analysis reveals a classical interferon signature induced by IFNλ4 in human primary cells

Impact of host genetic polymorphisms on vaccine induced antibody response

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