Hepatitis C Virus Diversity and Evolution in the Full Open-Reading Frame during Antiviral Therapy
Hepatitis C Virus Diversity and Evolution in the Full Open-Reading Frame during Antiviral Therapy
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DOI：
10.1371/journal.pone.0002123
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发表时间：
2008-05-07
期刊：
影响因子：
3.7
通讯作者：
Tavis, John E.
中科院分区：
文献类型：
--
作者：
Cannon, Nathan A.;Donlin, Maureen J.;Tavis, John E.
背景：聚乙二醇干扰素联合利巴韦林治疗丙型肝炎病毒（HCV）失败，约一半的基因型1患者。治疗失败的发生要么是无应答（病毒滴度的最小下降），要么是复发（治疗期间或治疗后病毒滴度反弹后的稳健初始应答）。HCV在遗传上是高度可变的。为了确定病毒遗传差异是否导致缓解和复发之间的差异，我们在完整开放阅读框HCV基因型1a共有序列中检查了患者间的遗传多样性和突变模式。方法/主要发现：对Virahep-C临床研究中的10名无缓解者和10名复发者进行了治疗前和治疗后序列分析。复发者治疗前患者间病毒NS 2和NS 3基因的多样性高于无应答者，复发者治疗后HCV 10个基因中的大多数基因的多样性更高。复发者的治疗前多样性介于治疗无应答者和应答者之间。在氨基酸水平上的平均突变率仅为0.9%，并且在无应答者和复发者序列中发生了相似数量的突变，但复发者的NS 2中的突变比无应答者的保守性低。最后，两组之间阳性选择区域的数量和分布相似，尽管无应答者在E2中有更多的阳性选择灶。结论/意义：HCV序列在失败的抗病毒治疗期间出乎意料地稳定，无应答者和复发者序列在治疗期间都处于选择性压力下，NS 2的变异可能导致了无应答者和复发者组之间应答的差异。这些数据支持病毒遗传变异性在确定抗HCV治疗结果中的作用，其中那些距离最佳序列更远的序列不太能够抵抗基于干扰素的治疗的压力。
Background: Pegylated interferon plus ribavirin therapy for hepatitis C virus (HCV) fails in approximately half of genotype 1 patients. Treatment failure occurs either by nonresponse (minimal declines in viral titer) or relapse (robust initial responses followed by rebounds of viral titers during or after therapy). HCV is highly variable genetically. To determine if viral genetic differences contribute to the difference between response and relapse, we examined the inter-patient genetic diversity and mutation pattern in the full open reading frame HCV genotype 1a consensus sequences.Methodology/Principal Findings: Pre- and post-therapy sequences were analyzed for 10 nonresponders and 10 relapsers from the Virahep-C clinical study. Pre- therapy interpatient diversity among the relapsers was higher than in the nonresponders in the viral NS2 and NS3 genes, and post-therapy diversity was higher in the relapsers for most of HCV's ten genes. Pre- therapy diversity among the relapsers was intermediate between that of the non-responders and responders to therapy. The average mutation rate was just 0.9% at the amino acid level and similar numbers of mutations occurred in the nonresponder and relapser sequences, but the mutations in NS2 of relapsers were less conservative than in nonresponders. Finally, the number and distribution of regions under positive selection was similar between the two groups, although the nonresponders had more foci of positive selection in E2.Conclusions/Significance: The HCV sequences were unexpectedly stable during failed antiviral therapy, both nonresponder and relapser sequences were under selective pressure during therapy, and variation in NS2 may have contributed to the difference in response between the nonresponder and relapser groups. These data support a role for viral genetic variability in determining the outcome of anti-HCV therapy, with those sequences that are more distant from an optimal sequence being less able to resist the pressures of interferon-based therapy.