Why is the interferon sensitivity-determining region (ISDR) system useful in Japan?

Nakano, Isao; Fukuda, Yoshihide; Katano, Yoshiaki; Nakano, Satoshi; Kumada, Takashi; Hayakawa, Tetsuo

doi:10.1016/s0168-8278(99)80254-2

Cited by 59 publications

(81 citation statements)

References 23 publications

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“…This sequence has been termed the interferon sensitivity-determining region (ISDR). These results were then confirmed by other Japanese studies [11][12][13][14][15] , but were never in accordance with most Western European [16][17][18][19][20] and American studies [21][22][23] , in which most of the ISDR sequences harbored an intermediate profile.…”

Section: Introductionsupporting

confidence: 64%

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Veillon

Payan²,

Guillou‐Guillemette³

et al. 2007

WJG

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AIM:To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNAdependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear.METHODS: HCV quasispecies were studied by cloning and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-α2b for 3 mo followed by IFN-α2b alone or combined IFN-R therapy for 9 additional months. Patients were categorized intro two groups based on their response to the treatments: 7 with sustained virological response (SVR) (quasispecies = 150) and 3 non-responders (NR) to IFN-R (quasispecies = 106). RESULTS:Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispecies during therapy. Analysis of amino acids substitutions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate the two groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients. CONCLUSION:These results suggest that detailed molecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection.

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Section: Introductionsupporting

confidence: 64%

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Veillon

Payan²,

Guillou‐Guillemette³

et al. 2007

WJG

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“…Enomoto et al (6,7) first demonstrated that amino acid mutations of the nonstructural protein 5A (NS5A) of HCV-1b in a region between residues 2209 and 2248 were associated with improved responsiveness to IFN in Japanese patients, and the region has therefore been designated as the IFN sensitivity-determining region (ISDR). This observation was subsequently confirmed by other research groups mostly in Japan (2,3,21,28,34). However, several reports from Europe and the United States failed to show the correlation between ISDR mutations and IFN responsiveness (5,11,22,32), challenging the ISDR hypothesis.…”

mentioning

confidence: 59%

Correlation between Mutations in the Interferon Sensitivity-Determining Region of NS5A Protein and Viral Load of Hepatitis C Virus Subtypes 1b, 1c, and 2a

Lusida

Nagano-Fujii²,

Nidom

et al. 2001

J Clin Microbiol

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In the present study, we analyzed the possible relationship between interferon (IFN) sensitivity-determining region (ISDR) sequence variation of various hepatitis C virus (HCV) subtypes and serum HCV titers in Indonesian patients without IFN treatment. The viremia titers (mean ؎ standard deviation) of HCV subtype 1b (HCV-1b) isolates with low (three or fewer) and high (four or more) numbers of ISDR mutations were 5.4 ؎ 0.6 and 4.2 ؎ 0.9 log 10 RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Similarly, the viremia titers of HCV-1c isolates with low and high numbers of ISDR mutations were 5.3 ؎ 0.6 and <3.0 ؎ 0.0 log 10 RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Also, the virus titers of HCV-2a isolates with low and high numbers of ISDR mutations were 4.3 ؎ 0.7 and 3.5 ؎ 0.4 log 10 RNA copies/ml, respectively, with the difference between the two groups being statistically significant (P < 0.01). Thus, our results demonstrated that virus load in Indonesian patients infected with HCV-1b, HCV-1c, or HCV-2a correlated inversely with the number of mutations in the ISDR sequence, implying the possibility that the ISDR sequence plays an important role in determining the levels of HCV viremia.Hepatitis C virus (HCV) readily establishes a chronic persistent infection that often results in chronic hepatitis and more deteriorating disease such as liver cirrhosis and hepatocellular carcinoma (14). HCV is phylogenetically classified into at least six clades (formerly called genotypes), each of which can be further divided into a number of subtypes (4,26,30). We have previously reported the prevalence of each HCV subtype, including HCV subtype 1c (HCV-1c) (formerly referred to as HCV-1d), among various clinical populations in Surabaya, Indonesia (13, 31). HCV-1c has been found almost exclusively in Indonesia (12,13,23) and shown to be associated with high viral load and poor prognosis (18,31).Interferon (IFN) is the most successful therapeutic agent for the treatment of chronic hepatitis C, although less than half of the patients treated with IFN show sustained responses with eradication of the virus. It is now recognized that HCV viral load in the serum and the HCV genotype and/or quasispecies complexity as well as sequence diversity of particular regions of the viral genome may predict the effectiveness of IFN therapy (2,3,10,16,25,27). Lower pretreatment serum HCV RNA levels have been shown to be associated with a better response to IFN therapy. Patients infected with HCV-1b tend to exhibit poor IFN responsiveness compared with those infected with HCV-2a. Enomoto et al. (6,7) first demonstrated that amino acid mutations of the nonstructural protein 5A (NS5A) of HCV-1b in a region between residues 2209 and 2248 were associated with improved responsiveness to IFN in Japanese patients, and the region has therefore been designated as the IFN sensitivity-determining region (ISDR). This obser...

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“…Our results from this study confirmed the close association between amino-acid substitutions in the ISDR and efficacy of IFN in Japanese patients. 12,13,[16][17][18] The relationship between the number of amino-acid substitutions in the ISDR and virus load and the independent contribution of these 2 factors to prediction of the outcome of IFN treatment were also confirmed by 3 different quantitation methods. However, as we reported previously, 16 there are exceptional patients who respond poorly to IFN despite the presence of multiple amino-acid substitutions in the ISDR and low virus load, and vice versa.…”

Section: Discussionmentioning

confidence: 97%

Association of Amino Acid Sequence in the Pkr–Eif2 Phosphorylation Homology Domain and Response to Interferon Therapy

et al. 2000

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Hepatitis C virus (HCV) usually causes chronic infection, which can result in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. [1][2][3][4] The only drug that effectively reduces the virus load is interferon (IFN), but complete eradication of the virus occurs in only some treated patients. [5][6][7][8] Currently, genotype 1b and a high virus titer are well-established predictive factors of a poor response to IFN. 9-11 Enomoto et al., 12,13 recently reported that amino-acid-sequence substitutions in a 40 amino acid stretch (codons 2209-2248) in the NS5A region of HCV genotype 1b are tightly associated with the outcome of IFN therapy, and designated this region as the IFN-sensitivity-determining-region (ISDR). A recent in vitro study by Gale et al., 14,15 suggested that the ISDR (or the amino-acid stretch adjacent to it) binds to IFN-inducible protein kinase (PKR), and inhibits its action as a blocker of viral protein synthesis. However, whether this region is really predictive of the outcome of IFN therapy is still controversial. A few Japanese studies have confirmed the fact that HCV virus with multiple amino-acid substitutions in this region is sensitive to IFN, [16][17][18][19] but studies from Europe and the United States have reported that such an association was not observed in their patients. [20][21][22][23][24][25][26][27][28] One recent study from Europe did however show the partial predictive value of amino-acid analysis in the ISDR. 29,30 More recently, Taylor et al. 31 reported that HCV E2 protein contains a 12 amino-acid-sequence domain that is highly homologous to the autophosphorylation site of PKR and initiation factor eIF2 ␣, a target of PKR (the PKR-eIF2 ␣ phosphorylation homology domain [PePHD]). They showed that the E2 protein inhibited the kinase activity of PKR and blocked its inhibitory effect on protein synthesis and cell growth, suggesting that the interaction of E2 and PKR may be one of the mechanisms by which HCV circumvents the antiviral effect of IFN. They also reported that E2 proteins with a PePHD sequence identical to genotypes 2 and 3 HCV, which are known IFN-sensitive genotypes, showed only a weak inhibitory effect against PKR activity.The above results prompted us to investigate whether aminoacid substitutions in the PePHD domain correlate with outcome of IFN therapy in patients with genotype 1b HCV infection. Furthermore, we sequenced multiple clones of PePHD in patients before and during IFN to investigate the behavior of HCV quasispecies in this region and to determine whether an IFN-resistant strain was selected during IFN treatment. We also studied amino-acid sequences of the ISDR and virus load in the same population using 3 different quantitative measurements of HCV, namely, branched (b)DNA assay and real time Abbreviations: ALT, alanine transaminase; HCV, hepatitis C virus; ISDR, interferon sensitivity determining region; PCR, polymerase chain reaction, PePHD, PKR-eIF2 ␣ phosphorylation homology domain; RT, reverse transcription; PKR, IFN-inducible prot...

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Why is the interferon sensitivity-determining region (ISDR) system useful in Japan?

Cited by 59 publications

References 23 publications

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Correlation between Mutations in the Interferon Sensitivity-Determining Region of NS5A Protein and Viral Load of Hepatitis C Virus Subtypes 1b, 1c, and 2a

Association of Amino Acid Sequence in the Pkr–Eif2 Phosphorylation Homology Domain and Response to Interferon Therapy

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