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-? therapy

Abstract

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 ...

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

“…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.…”

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

“…51 Recently, we found a significant association between the mutation in the NS5A2209-2248 of HCV-1b (ISDR) and the response to interferon alfa 13 or beta. 39 ISDR mutations are also shown to be related to the serum HCV-RNA levels. 13,16 Therefore, in HCV-2 infection, the amino acid changes in the homologous region might also be associated with the effect of interferon therapy.…”

“…10,38,39 It was suggested that HCV-2b is also more sensitive to interferon than HCV-1b. 12,40 However, these reports were based on a small number of patients with HCV-2.…”

“…The present findings of HCV-2a infection on the interrelationship among interferon efficacy, viral load, and NS5A mutations are consistent with the observation seen in HCV1b. 13,16,39 The mechanism of this interrelation is still unclear, but an association between the amino acid changes in NS5A and reduced serum HCV-RNA level suggest an important role of the NS5A protein in the proliferation of HCV. Otherwise, the NS5A protein would confer the resistance to antiviral effects of interferon.…”

Efficacy and Safety of Combination Therapy of Natural Human Interferon Beta and Ribavirin in Chronic Hepatitis C patients

“…Moreover, IFN-beta could be given to elderly patients aged !70 years because of the mild side effects (10). However, IFN-beta monotherapy does not result in a satisfactory outcome in patients with genotype 1b and a high virus load (11,12). The combination therapy of IFN-beta and ribavirin has the possibility to show the strong effect for hepatitis C virus (HCV) and mild side effects originating from the treatment (13)(14)(15).…”