近日，《感染、遗传和进化》（Infection, Genetics and Evolution）杂志在线发表了中国科学院上海巴斯德研究所钟劲研究组与上海瑞金医院感染科谢青教授研究组合作研究的最新成果。他们通过对两例不同类别的干扰素治疗失败的慢性丙肝患者进行长期随访，从病毒学角度深入研究了各随访时间点丙型肝炎病毒（HCV）全长基因序列的变异和进化情况。结果提示，治疗中反弹（breakthrough）患者中HCV的变异有可能是丙肝治疗失败的重要因素，这一发现将有助于进一步揭示难治性丙型肝炎的分子机制，为改善临床疗效提供新的思路。
Infection, Genetics and Evolution
Article in Press, Corrected Proof - Note to users
doi:10.1016/j.meegid.2010.11.011 | How to Cite or Link Using DOI
Viral sequence evolution in Chinese genotype 1b chronic hepatitis C patients experiencing unsuccessful interferon treatment
Xiaogang Xianga, b, Jie Lub, Zhixia Donga, Huijuan Zhoua, Wanyin Taob, Qing Guoa, Xiaqiu Zhoua, Shisan Baoc, Qing Xiea, b, , and Jin Zhongb, ,
a Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Road, Shanghai 20005, China
b Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai 200025, China
c Discipline of Pathology (D06), Bosch Institute and School of Medical Sciences, The University of Sydney, New South Wales 2006, Australia
Received 6 July 2010; revised 12 November 2010; accepted 24 November 2010. Available online 13 December 2010.
Abstract
The efficiencies of IFN-α based therapy in chronic genotype 1b HCV patients are still unsatisfied to date. The mechanisms underlining treatment failure remain unclear and controversial. To investigate HCV sequence evolution in unsuccessfully treated genotype 1b patients before, during and after the therapy, full-length open-reading-frame of HCV genomes at week 0, week 48 and year 5 in one breakthrough and one nonresponse patients were amplified by reverse transcription (RT)-nested-PCR and sequenced. Mutations were scored and analyzed according to their locations in the HCV genome. HCV sequences in the breakthrough patient displayed significantly more mutations during the one-year therapy than that in the nonresponse patient, with p7 and NS2 encoding regions having the highest mutation rates. Most of the mutations selected during the therapy phase in the breakthrough patient were maintained and few new mutations arose in the four-year post-therapy phase, suggesting these mutations might not compromise viral fitness. Altogether our data suggest that mutations occurred during the therapy phase in the breakthrough patient are likely driven by the action of interferon and ribavirin, and these mutations may have important effects on the responses to interferon based therapy in genotype 1b HCV patients.
Research highlights
Longitudinal sequencing analysis of HCV genomes in unsuccessfully treated patients. HCV genome mutation rate in the breakthrough patient was high during the therapy. HCV genome mutation rate in the nonresponse patient was low during the therapy. Most HCV mutations in the breakthrough patient were kept in the post-therapy phase. Viral mutations may account for interferon resistance in HCV breakthrough patients.
Keywords: Hepatitis C virus; Interferon therapy; Sustained virological response; Breakthrough; Nonresponse; Sequence evolution