The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus–induced microRNAs

McFarland, Adelle P.; Horner, Stacy M.; Jarret, Abigail; Joslyn, Rochelle C; Bindewald, Eckart; Shapiro, Bruce A.; Delker, Don A.; Hagedorn, Curt H.; Carrington, Mary; Gale, Michael; Savan, Ram

doi:10.1038/ni.2758

Cited by 139 publications

(156 citation statements)

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“…We genotyped all samples (n = 33) for 3 genetic variants associated with HCV clearance: the intronic rs12979860-C/T (29,30) and exonic rs368234815-TT/ΔG (31,32) of IFNL4 and the 3′ untranslated region (UTR) rs4803217-T/G of IFNL3 (Supplemental Tables 1 and 5 and ref. 33). 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.…”

Section: Resultsmentioning

confidence: 99%

“…Genotypes of IFNL4 variants (intronic rs12979860-C/T, previously known as the IFNL3 [IL28B] marker and exonic rs368234815-TT/ΔG) and a 3′ UTR IFNL3 variant (rs4803217-T/G) have been shown to affect treatment outcome for HCV infection and correlate with intrahepatic ISG expression, transcript stability of IFNL3, and balance of the innate immune system in response to HCV infection (28,31,33,(44)(45)(46). Although we genotyped these markers in our subjects (Supplemental Tables 1 and 5), the incidence of favorable IFNL3 and IFNL4 genotypes was too in- Statistical analysis of data in Figure 3C.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we were unable to detect the presence of pDCs as a potential source of IFNA2 induction during treatment by immunohistochemistry in pretreatment or EOT liver. Analysis of cell type-specific IFN production in situ was limited by tissue availability, but this analysis should be considered in subsequent DAA clinical trials as an invaluable tool for investigating the differential roles of diverse innate immune cells in the liver (43).Genotypes of IFNL4 variants (intronic rs12979860-C/T, previously known as the IFNL3 [IL28B] marker and exonic rs368234815-TT/ΔG) and a 3′ UTR IFNL3 variant (rs4803217-T/G) have been shown to affect treatment outcome for HCV infection and correlate with intrahepatic ISG expression, transcript stability of IFNL3, and balance of the innate immune system in response to HCV infection (28,31,33,(44)(45)(46). Although we genotyped these markers in our subjects (Supplemental Tables 1 and 5), the incidence of favorable IFNL3 and IFNL4 genotypes was too in- Statistical analysis of data in Figure 3C.…”

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confidence: 99%

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

Meissner¹,

Wu²,

Osinusi³

et al. 2014

J. Clin. Invest.

189

192

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Meissner¹,

Wu²,

Osinusi³

et al. 2014

J. Clin. Invest.

189

192

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“…A close association between TA length and the induction of the IL-28B gene has been reported in a Japanese population [76], but not in a South East Asian population, suggesting that ethnic differences may have some effect. Other investigators have reported that the stability of IL-28B transcripts may be influenced by the specific determining region in the 3 0 -untranslated region of the HCV genome [77].…”

Section: Subsets/bdca3 1 Dcs In Acute Hcv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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“…The minor allele of a further SNP within exon 2, rs117648444, causes an amino acid substitution (P70S), leading to a functionally impaired IFNL4 protein. Transcription of IFNL3 has been shown to be related to rs12979860 [58] and ss469415590 [57], as well as to an SNP within the 3′-UTR which was shown to mediate miRNA-driven mRNA decay [60]. …”

Section: Interferonsmentioning

confidence: 99%

Activation of Type I and Type III Interferons in Chronic Hepatitis C

Mihm

2015

J Innate Immun

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Infection with hepatitis C virus (HCV) results in chronic and progressive liver disease. Persistency rates add up to 85%. Despite recognition of the virus by the human host in peripheral blood and in the liver, immune response appears to be ineffective in clearing infection. The ability to spontaneously eradicate the virus as well as the outcome of infection upon therapy with human recombinant interferon-α (IFN-α) was found to correlate most closely with genetic variations within the region encoding the IFN-λ genes, as revealed by genome-wide association studies on main ethnic populations in 2009. This review summarizes the induction of type I and type III IFN genes and their effectors, the IFN-stimulated genes. It focusses on the in vivo situation in chronic HCV infection in man both in the peripheral blood compartment and in the liver. It also addresses the impact of genetic polymorphisms in the region of type III IFN genes on their activation. Finally, it discusses how antiviral drugs (i.e. IFN-α, ribavirin and the direct-acting antivirals) may complementarily control the activation of endogenous IFNs and succeed in combatting infections.

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The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus–induced microRNAs

Cited by 139 publications

References 52 publications

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

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

Host–virus interactions in hepatitis B and hepatitis C infection

Activation of Type I and Type III Interferons in Chronic Hepatitis C

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