Hepatitis C therapeutics: current status and emerging strategies

Tan, Seng‐Lai; Pause, Arnim; Shi, Yuguang; Sonenberg, Nahum

doi:10.1038/nrd937

Cited by 200 publications

(152 citation statements)

References 115 publications

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“…36 The commercial IFN-a preparations that are largely used for HCV therapy consist of IFN-a2a or IFN-a2b subtypes. 37 Some of these studies indicate that there is a positive IL10 association with susceptibility to chronic hepatitis C infection and resistance to combined antiviral therapy [38][39][40][41] and rapid fibrosis 39 while in others the association between IL10 promoter region SNPs and viral clearance or persistent infection or severity of disease was not found. [42][43][44] These results further indicated the importance of evaluating HCV clearance in a large set of patients for IL10, its neighboring paralogs, and other genes in the region.…”

Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

et al. 2005

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Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (7300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P ¼ 0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P ¼ 0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.

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Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

et al. 2005

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“…3 The commercial IFN preparations that are largely used for HCV therapy consist of IFN-␣2a or IFN-␣2b subtypes. 4 The type I IFNs bind to a common receptor that is expressed on the surface of target cells. Receptor engagement leads to the activation of the Jak-STAT signaling pathway through the actions of the Jak1 and Tyk2 protein kinases, which catalyze phosphorylation events leading to the activation and heterodimerization of the signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2.…”

mentioning

confidence: 99%

Effector Genes of Interferon Action Against Hepatitis C Virus

Gale

2003

Hepatology

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C urrent therapy of chronic hepatitis C virus (HCV) infection is based on type I interferon (IFN) preparations. 1 The IFNs comprise a class of related cytokines that induce antiviral and immunomodulatory actions of their target cells. 2,3 The type I IFNs include multiple IFN-␣ species and a single IFN-␤ species ( Fig. 1), and IFN-␥ is the single type II IFN. 3 The commercial IFN preparations that are largely used for HCV therapy consist of IFN-␣2a or IFN-␣2b subtypes. 4 The type I IFNs bind to a common receptor that is expressed on the surface of target cells. Receptor engagement leads to the activation of the Jak-STAT signaling pathway through the actions of the Jak1 and Tyk2 protein kinases, which catalyze phosphorylation events leading to the activation and heterodimerization of the signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2. 2 STAT3 has also been shown to respond to type I IFN receptor signaling and is proposed to link IFN signaling events with cell growth regulation and the phosphatidylinositol 3-kinase pathway. 5,6 The STAT1/2 heterocomplex translocates to the cell nucleus, where it associates with p48/IRF-9 to form interferonstimulated gene factor 3 (ISGF3). 2 ISGF3 binds to the IFN-stimulated response element (ISRE) of cellular genes, known as IFN-stimulated genes (ISGs), leading to their induced expression and synthesis of the ISG products. Sequence motifs within the ISRE also serve as target sites for interferon regulatory factors (IRFs), whose actions and ISRE-binding properties contribute to define the overall spectrum and duration of ISG expression. 2,3 It is the biochemical actions of the ISG products that impart the primary therapeutic actions of IFN against HCV infection. However, IFN therapy continues to be problematic, because even under the best conditions, contemporary treatment protocols show limited efficacy such that only about one half of all treated patients exhibit sustained viral clearance. 1,4 The reasons for this limited efficacy are unclear, but are likely to involve both viral and host factors that ultimately affect the level and extent of ISG expression and function induced during the course of IFN therapy. [7][8][9][10] Results from microarray expression studies indicate that the human genome encodes hundreds, if not thousands of functionally diverse ISGs, some of which are known to direct antiviral actions. 11 However, the complete spectrum of ISGs has not been defined nor have the ISGs that impart control of HCV replication been identified. The refinement and further improvement of IFN therapy for chronic HCV infection will no doubt come from a better understanding of how IFN affects the infected hepatocyte and other target cells. This requires defining the spectrum and kinetics of ISG expression under in vivo conditions of IFN therapy and categorizing ISG expression patterns within patients who respond to therapy and in those patients who fail IFN therapy. In vivo studies that couple analyses of viral decay kinetics with microarray profili...

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“…In effect, the proteolysis of IPS-1 attenuates both the production of α/β IFN and disrupts a critical amplification loop of α/β IFN signaling, thus suppressing innate immune defenses to HCV infection. Our studies reveal an immunomodulatory potential of NS3/4A protease inhibitors toward the therapeutic restoration of innate immune defenses against HCV [35,37].…”

Section: Disruption Of Rig-i Signaling By the Hcv Ns3/4a Proteasementioning

confidence: 79%

Innate immune evasion by hepatitis C virus and West Nile virus

Keller

Johnson

Erickson

et al. 2007

Cytokine & Growth Factor Reviews

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Antiviral immunity in mammals involves several levels of surveillance and effector actions by host factors to detect viral pathogens, trigger α/β interferon production, and to mediate innate defenses within infected cells. Our studies have focused on understanding how these processes are regulated during infection by hepatitis C virus (HCV) and West Nile virus (WNV). Both viruses are members of the Flaviviridae and are human pathogens but they each mediate a very different disease and course of infection. Our results demonstrate common and unique innate immune interactions of each virus that govern antiviral immunity, and demonstrate the central role of α/β interferon immune defenses in controlling the outcome of infection.

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Hepatitis C therapeutics: current status and emerging strategies

Cited by 200 publications

References 115 publications

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

Effector Genes of Interferon Action Against Hepatitis C Virus

Innate immune evasion by hepatitis C virus and West Nile virus

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