Interferon lambda 4 variant rs12979860 is not associated with RAV NS5A Y93H in hepatitis C virus genotype 3a

Pedergnana, Vincent; Smith, David A.; Klenerman, Paul; Barnes, Eleanor; Spencer, Chris C. A.; Ansari, Azim

doi:10.1002/hep.28533

Cited by 5 publications

(4 citation statements)

References 3 publications

(2 reference statements)

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“…An association between IFNL4 and amino-acid variability in the same region of NS5B protein, has previously been reported in a candidate gene study 32 in a single source infection cohort. IFNL4 has also been associated with a viral mutation associated with DAA resistance in HCV genotype 1 infection 44 although this association has not been replicated in our HCV genotype 3 cohort 45 . The additional signals in NS5B protein associated with IFNL4 genotypes (or HLA alleles) at a 5% FDR did not replicate ( P > 0.05) potentially due to a lack of power resulting from the smaller sample size of the replication cohort and/or the fact that the phylogenetically corrected Fisher’s exact tests could not be performed in an equivalent way (only NS5B sequences were available in the replication cohort).…”

Section: Discussionmentioning

confidence: 63%

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

et al. 2017

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Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. We use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals chronically infected with HCV, predominately genotype 3. We show that both HLA alleles and interferon lambda innate immune system genes drive viral genome polymorphism, and that IFNL4 genotypes determine HCV viral load through a mechanism that is dependent on a specific polymorphism in the HCV polyprotein. We highlight the interplay between innate immune responses and the viral genome in HCV control.

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Section: Discussionmentioning

confidence: 63%

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

et al. 2017

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“…This observation implies viral adaptation to the host depending on IFNL3/IFNL4 allelic status. Although these findings are presently limited to genotype 1b viruses ( Akamatsu et al, 2015 ; Pedergnana et al, 2016 ; Peiffer et al, 2016 ), they provide a proof of principle for the hypothesis that human genetic diversity exerted a selective pressure on HCV and possibly contributed to the radiation of the seven genotypes.…”

Section: Discussionmentioning

confidence: 86%

Evolutionary Analysis Provides Insight Into the Origin and Adaptation of HCV

et al. 2018

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Hepatitis C virus (HCV) belongs to the Hepacivirus genus and is genetically heterogeneous, with seven major genotypes further divided into several recognized subtypes. HCV origin was previously dated in a range between ∼200 and 1000 years ago. Hepaciviruses have been identified in several domestic and wild mammals, the largest viral diversity being observed in bats and rodents. The closest relatives of HCV were found in horses/donkeys (equine hepaciviruses, EHV). However, the origin of HCV as a human pathogen is still an unsolved puzzle. Using a selection-informed evolutionary model, we show that the common ancestor of extant HCV genotypes existed at least 3000 years ago (CI: 3192–5221 years ago), with the oldest genotypes being endemic to Asia. EHV originated around 1100 CE (CI: 291–1640 CE). These time estimates exclude that EHV transmission was mainly sustained by widespread veterinary practices and suggest that HCV originated from a single zoonotic event with subsequent diversification in human populations. We also describe a number of biologically important sites in the major HCV genotypes that have been positively selected and indicate that drug resistance-associated variants are significantly enriched at positively selected sites. HCV exploits several cell-surface molecules for cell entry, but only two of these (CD81 and OCLN) determine the species-specificity of infection. Herein evolutionary analyses do not support a long-standing association between primates and hepaciviruses, and signals of positive selection at CD81 were only observed in Chiroptera. No evidence of selection was detected for OCLN in any mammalian order. These results shed light on the origin of HCV and provide a catalog of candidate genetic modulators of HCV phenotypic diversity.

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“…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). We identified the association of 11 sites in the HCV polyprotein with IFNL4 genotypes, including one (serine vs. nonserine at position 2414 in NS5A) that was also associated with viral load in vivo and viral fitness in vitro …”

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confidence: 99%

“…We identified the association of 11 sites in the HCV polyprotein with IFNL4 genotypes, including one (serine vs. nonserine at position 2414 in NS5A) that was also associated with viral load in vivo and viral fitness in vitro. (24) Based on these data, we hypothesized that host IFNL4 genotype might particularly affect viral outcome in patients with cirrhosis treated with the shortest protocol (16 weeks). We aimed to test whether transcriptional changes in the host response were detectable in blood and linked to outcome.…”

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confidence: 99%

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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Interferon lambda 4 variant rs12979860 is not associated with RAV NS5A Y93H in hepatitis C virus genotype 3a

Cited by 5 publications

References 3 publications

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

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

Evolutionary Analysis Provides Insight Into the Origin and Adaptation of HCV

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

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