Mutations in the Nonstructural Protein 5a Gene and Response to Interferon in Patients with Chronic Hepatitis C Virus 1b Infection

Enomoto, Nobuyuki; Sakuma, Ikuo; Asahina, Yasuhiro; Kurosaki, Masayuki; Murakami, Takeshi; Yamamoto, Chikara; Ogura, Yuki; Izumi, Namiki; Marumo, Fumiaki; Sato, Chifumi

doi:10.1056/nejm199601113340203

Cited by 965 publications

(931 citation statements)

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“…NS5A is a viral factor that helps HCV establish a niche in the host cell by turning off the IFNa signaling pathway. 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.…”

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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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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“…These results HCV-1b and multiple mutations in the NS5A2209-2248 usuindicate that the mutant-type HCV-1b or HCV-2 are sen-ally have a beneficial response to IFN-a therapy. 18,19 It is not sitive to IFN-b as well as IFN-a. In conclusion, the deter-clear, however, whether these viral factors also correlate with mination of HCV genotypes, NS5A2209-2248 of HCV-1b the responses to IFN-b, because clinical studies with the and serum HCV-RNA levels may facilitate the selection standardized regimen of IFN-b have not been reported.…”

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confidence: 99%

“…Extraction of RNA, reverse-transcription, and PCR were performed on pretreatment sera as described previously. 19 HCV genotypes were determined by PCR using four sets of genotype-specific Among 40 patients, 22 were infected with HCV-1b, 13 with primers. 21 Serum HCV-RNA levels were determined by competitive HCV-2a, and 5 with HCV-2b.…”

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confidence: 99%

Analysis of Genotypes and Amino Acid Residues 2209 to 2248 of the Ns5a Region of Hepatitis C Virus in Relation to the Response to Interferon–β Therapy

et al. 1997

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The hepatitis C virus (HCV) is the major cause of chronic addition, we recently reported a close correlation be-non-A, non-B hepatitis, a disease that seldom resolves spontween the number of mutations in amino acid sequences taneously and that can progress to cirrhosis and hepatocellu-2209 to 2248 of the nonstructual protein 5A gene lar carcinoma over several decades. 1 The development of ef-(NS5A2209-2248) of HCV-1b and the response to IFN-a. fective treatments to eradicate HCV infection is of great In the present study, we analyzed these viral factors in medical importance. relation to the efficacy to IFN-b, another type I IFN. TheInterferon alfa (IFN-a) a type I IFN, has been used to treat pretreatment sera of 40 patients treated with IFN-b in-chronic hepatitis C throughout the world since the first report travenously at 6 MU daily for 42 days were studied. HCV of its beneficial effects in 1986. 2 IFN-b is also a type I IFN genotypes, serum HCV-RNA levels, and the amino acid that is commonly used in the treatment of acute and chronic sequence of NS5A2209-2248 in HCV-1b were determined. hepatitis C in Japan. [3][4][5] It has been believed that type I IFNs A sustained complete response to IFN therapy occurred bind to the same receptor; however, recent evidence suggests in none of the ten patients with the wild-type HCV-1b the existence of a second receptor-associated protein that is who had an NS5A2209-2248 sequence identical to the involved specifically in the IFN-b signaling pathway. 6 Inprototype HCV-1b and in none of the six patients with deed, in vitro experiments have shown that different type I the intermediate-type HCV-1b that had 1 mutation. In IFNs induce different biological responses. 7,8 Thus, IFN-a contrast, complete responses occurred in the following: and IFN-b may exhibit different characteristics in the treat-4 of 6 patients with the mutant-type HCV-1b that had ment of chronic hepatitis C. five to ten mutations; 6 of 13 patients with genotype 2aThe majority of clinical trials in hepatitis C have employed of HCV (HCV-2a); and 2 of 5 patients with genotype 2b recombinant or natural IFN-a and have shown that HCV of HCV (HCV-2b). Among patients with the mutant-type genotypes and serum HCV-RNA levels correlate with long-HCV-1b or genotype 2 of HCV (HCV-2) the rate of com-term beneficial responses to IFN-a. Thus, genotype 1b of HCV plete response was significantly higher (12 of 24 vs. 0 of (HCV-1b) has been found to be more resistant to IFN-a than 16 patients, P õ .001) and HCV-RNA levels were signifi-was genotype 2 of HCV (HCV-2), and patients with high cantly lower (4.5 [4.0-6.5] vs. 6 [4.5-6.5] log copies/mL, me-HCV-RNA levels were found to be more resistant to IFN-a dian [range]; P õ .001) compared with patients with the than were those with low HCV-RNA levels. 9-17 Furthermore, wild-or the intermediate-type HCV-1b. Patients with the we reported recently that the sensitivity to IFN-a in HCVmutant-type HCV-1b or HCV-2 whose HCV-RNA levels 1b correlates closely with the number of mutations in the ...

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“…NS5A harbors T-cell epitope and is not directly affected by neutralization [14]. A higher number of amino acid substitutions in the ISDR was strongly associated with a favorable response to IFN therapy in patients infected with genotype 1 HCV [15] and, according to Ishii et al in this journal [16], with a higher proportion of Th2 cells. Although the exact role of NS5A remains to be elucidated, this protein has been shown to bind a range of cellular signaling molecules that may affect numerous cellular pathways in HCV-infected cells, including the antiviral IFN-a response.…”

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confidence: 88%

The long way toward understanding host and viral determinants of therapeutic success in HCV infection

2012

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Mutations in the Nonstructural Protein 5a Gene and Response to Interferon in Patients with Chronic Hepatitis C Virus 1b Infection

Abstract: In patients with chronic HCV-1b infection, there is a substantial correlation between responses to interferon and mutations in the NS5A gene.

Cited by 965 publications

References 31 publications

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

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

Analysis of Genotypes and Amino Acid Residues 2209 to 2248 of the Ns5a Region of Hepatitis C Virus in Relation to the Response to Interferon–β Therapy

The long way toward understanding host and viral determinants of therapeutic success in HCV infection

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