Hepatitis C Virus non-structural 5A abrogates signal transducer and activator of transcription-1 nucleartranslocation induced by IFN-α through dephosphorylation

Gong, Guozhong; Cao, Jie; Jiang, Yong-Fang; Zhou, Yang; Liu, Bo

doi:10.3748/wjg.v13.i30.4080

Cited by 13 publications

(10 citation statements)

References 27 publications

(13 reference statements)

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“…In our study, substitutions N248H and E269K found in the "medium" lineage at p45 and S272P in the "low" lineage (mixed at p45 and dominant by p100) are located within the ISDR. Studies on the mechanisms by which NS5A counteracts IFN-␣ activity have not given conclusive results (91,(93)(94)(95)112).…”

Section: Discussionmentioning

confidence: 99%

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Perales

Beach

Gallego

et al. 2013

J Virol

172

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H epatitis C virus (HCV) infects an estimated 180 million people worldwide, and about 75% of newly infected patients progress toward a chronic infection, which constitutes a risk for severe liver diseases such as cirrhosis and hepatocarcinoma (1-4). HCV is a hepacivirus in the Flaviviridae family characterized by the error-prone replication and quasispecies dynamics typical of RNA viruses (2,(5)(6)(7). No vaccine is available to prevent HCV infections or disease, and the current standard of care treatment consists of the combination of pegylated alpha interferon (IFN-␣) and the purine nucleoside analogue ribavirin (1-␤-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) (8-10). Type I interferons (IFNs) such as IFN-␣ are members of a family of cytokines that constitute key components of the innate immune response to viruses, and their induction results in an antiviral state of the cell and suppression of viral replication (11)(12)(13)(14). Ribavirin is currently used to treat a number of human viral infections, and it can display multiple mechanisms of action, including enhancement of Th1 antiviral immune responses, upregulation of IFN-stimulated genes (ISGs), depletion of GTP pools, or viral RNA mutagenesis (see reviews in references 15, 16 and 17). However, on average only about 60% of the chronically infected patients show a sustained virological response to treatment with IFN-␣ plus ribavirin that results in virus clearance (18-21). The molecular and physiological bases of the therapeutic activity of the current combination treatment with IFN-␣ plus ribavirin are poorly understood. It might be possible to establish new treatment protocols based on recently developed directly acting antiviral agents (DAAs), with or without .Highly variable viruses exploit a number of strategies to counteract selective constraints intended to prevent their replication (reviewed in reference 7). Mutations that confer resistance to DAAs generally map in the target protein or in a protein that interacts with the target (28-30). However, the complexity of the cellular IFN response pathway is expected to require greater diversity of viral resistance mutations. Current evidence suggests that the response of HCV to IFN-␣-based therapy is influenced by several host (i.e., interleukin-28B [IL-28B] gene polymorphisms) and viral genetic (i.e., viral genotype and population complexity) factors (31-37).The advent of cell culture systems for sustained replication of HCV offers new prospects to approach the evolutionary dynamics of HCV and the host cell-virus relationship, including the anti-HCV activity of IFN-␣. Using these systems, Garaigorta and Chisari documented that HCV-induced protein kinase R (PKR) phosphorylation inhibited translation of IFN-stimulated genes (ISGs) in infected hepatocytes (38). Here we describe the adaptation of the HCV replication system of genotype 2a (39-41) to perform serial passages of HCV in the Huh-7.5 hepatocyte cell line with sustained, efficient viral replication for at least 100 serial passages. This cell ...

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Section: Discussionmentioning

confidence: 99%

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Perales

Beach

Gallego

et al. 2013

J Virol

172

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“…27 The sequence of a certain NS5A region, called the interferon sensitivity-determining region, 28 is highly associated with the final outcome of IFNa therapy. Furthermore, experimental evidence suggests that the function of NS5A includes abrogation of STAT-1 translocation, 29 suppression of STAT-1 phosphorylation 30 and repression of the protein kinase R protein kinase. [31][32][33] Because of its important function in controlling HCV replication, many molecules have been designed to target NS5A, some of which have exhibited promising treatment outcomes in clinical research.…”

Section: Ifn-a-induced Trim22 Interrupts Hcv Replicationmentioning

confidence: 99%

Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A

et al. 2015

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TRIM22, a tripartite-motif (TRIM) protein, is upregulated upon interferon alpha (IFNa) administration to hepatitis C virus (HCV)-infected patients. However, the physiological role of TRIM22 upregulation remains unclear. Here, we describe a potential antiviral function of TRIM22's targeting of the HCV NS5A protein. NS5A is important for HCV replication and for resistance to IFNa therapy. During the first 24 h following the initiation of IFNa treatment, upregulation of TRIM22 in the peripheral blood mononuclear cells (PBMCs) of HCV patients correlated with a decrease in viral titer. This phenomenon was confirmed in the hepatocyte-derived cell line Huh-7, which is highly permissive for HCV infection. TRIM22 over-expression inhibited HCV replication, and Small interfering RNA (siRNA)-mediated knockdown of TRIM22 diminished IFNa-induced anti-HCV function. Furthermore, we determined that TRIM22 ubiquitinates NS5A in a concentration-dependent manner. In summary, our results suggest that TRIM22 upregulation is associated with HCV decline during IFNa treatment and plays an important role in controlling HCV replication in vitro.

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“…HCV core prevents phosphorylation of STAT1 in response to IFN-α [17] and NS5A prevents translocation of pSTAT1 to the nucleus [18]. Shorter telomeres are associated with defective activation of STAT5 in mouse macrophages [19].…”

Section: Introductionmentioning

confidence: 99%

γ-H2AX+CD8+ T lymphocytes cannot respond to IFN-α, IL-2 or IL-6 in chronic hepatitis C virus infection

Hoare

Shankar

Shah

et al. 2013

Journal of Hepatology

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Background & AimsAge is the dominant prognostic factor influencing the natural history of hepatitis C virus (HCV) infection and treatment response. Accelerated lymphocyte telomere shortening in HCV infection correlates with adverse clinical outcomes. Critical telomere shortening generates double-stranded DNA breaks (DSB) inducing the DNA damage response, leading to replicative senescence. The phenotype and function of CD8+ T lymphocytes and the in vitro response to IFN-α in relation to the DNA damage response were investigated in patients with chronic HCV infection.MethodsCD8+ T lymphocytes with DSB were identified by expression of γ-H2AX (Ser-139) in 134 HCV-exposed subjects and 27 controls. Telomere length was determined by flow-FISH; cytokine expression by intracellular cytokine staining; in vitro responses to IFN-α, IL-2 or IL-6 by phospho-STAT1 (Y701) or phospho-STAT5 (Y694) expression.ResultsThe proportion of circulating CD8 + γ-H2AX+ T lymphocytes rose with increasing fibrosis stage (p = 0.0023). CD8 + γ-H2AX+ T lymphocytes were enriched in liver compared to blood (p = 0.03). CD8 + γ-H2AX+ T lymphocytes demonstrated increased IFN-γ (p = 0.02) and reduced IL-2 expression (p = 0.02). CD8 + γ-H2AX+ T lymphocytes failed to phosphorylate STAT1 in response to IFN-α compared to unfractionated CD8+ T lymphocytes (p <0.0001). More widespread failure of Jak/Stat signalling in CD8 + γ-H2AX+ T lymphocytes was suggested by impaired phosphorylation of STAT1 with IL-6 (p = 0.002) and STAT5 with IL-2 (p = 0.0039) compared to unfractionated CD8+ T-lymphocytes.ConclusionsIn chronic HCV infection, CD8 + γ-H2AX+ T lymphocytes are highly differentiated with shortened telomeres, are more frequent within the liver, are associated with severe fibrosis and fail to activate Jak/Stat pathways in response to IFN-α, IL-2 or IL-6, perhaps explaining treatment failure in those with severe fibrosis.

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Hepatitis C Virus non-structural 5A abrogates signal transducer and activator of transcription-1 nucleartranslocation induced by IFN-α through dephosphorylation

Cited by 13 publications

References 27 publications

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A

γ-H2AX+CD8+ T lymphocytes cannot respond to IFN-α, IL-2 or IL-6 in chronic hepatitis C virus infection

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