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Journal of Virology, July 2008, p. 6644-6653, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.02231-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of Hepatitis C Virus Genotype 1 and Their Relationships to Pegylated Interferon-Ribavirin Treatment Responses{triangledown}

P. Muñoz de Rueda, J. Casado, R. Patón, D. Quintero, A. Palacios, A. Gila, R. Quiles, J. León, A. Ruiz-Extremera, and J. Salmerón*

San Cecilio University Hospital, Gastroenterology Unit and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Granada, Spain

Received 15 October 2007/ Accepted 21 April 2008

Mutations in several subgenomic regions of hepatitis C virus (HCV) have been implicated in influencing the response to interferon (IFN) therapy. Sequences within HCV NS5A (PKR binding domain [PKRBD], IFN sensitivity-determining region [ISDR], and variable region 3 [V3]) were analyzed for the pretreatment serum samples of 60 HCV genotype 1-infected patients treated with pegylated IFN plus ribavirin (1b, n = 47; 1a, n = 13) but with different treatment outcomes, those with sustained virologic responses (SVR; n = 36) or nonresponders (NR; n = 24). Additionally, the sequence of the PKR/eIF-2{alpha} phosphorylation homology domain (E2-PePHD) region was determined for 23 patients (11 SVR and 12 NR). The presence of >4 mutations in the PKRBD region was associated with SVR (P = 0.001) and early virologic responses (EVR; 12 weeks) (P = 0.037) but not rapid virologic responses (4 weeks). In the ISDR, the difference was almost statistically significant (68% of SVR patients with mutations versus 45% without mutations; P = 0.07). The V3 region had a very high genetic variability, but this was not related to SVR. Finally, the E2-PePHD (n = 23) region was well conserved. The presence of >4 mutations in the PKRBD region (odds ratio [OR] = 9.9; P = 0.006) and an age of ≤40 years (OR = 3.2; P = 0.056) were selected in a multivariate analysis as predictive factors of SVR. NS5A sequences from serum samples taken after 1 month of treatment and posttreatment were examined for 3 SVR and 15 NR patients to select treatment-resistant viral subpopulations, and it was found that in the V3 and flanking regions, the mutations increased significantly in posttreatment sera (P = 0.05). The genetic variability in the PKRBD (>4 mutations) is a predictive factor of SVR and EVR in HCV genotype 1 patients treated with pegylated IFN and ribavirin.

* Corresponding author. Mailing address: Hospital Universitario San Cecilio, Ciberehd, Unidad Clínica de Aparato Digestivo, Avd. Dr. Oloriz 16, 18012 Granada, Spain. Phone: (34) 958240719. Fax: (34) 958284920. E-mail: fsalmero{at}ugr.es

{triangledown} Published ahead of print on 30 April 2008.

Journal of Virology, July 2008, p. 6644-6653, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.02231-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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