Genetic Diversity and Selective Pressure in Hepatitis C Virus Genotypes 1-6: Significance for Direct-Acting Antiviral Treatment and Drug Resistance.
Genetic Diversity and Selective Pressure in Hepatitis C Virus Genotypes 1-6: Significance for Direct-Acting Antiviral Treatment and Drug Resistance.
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DOI：
10.3390/v7092857
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发表时间：
2015-09-16
期刊：
影响因子：
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通讯作者：
Theys K
中科院分区：
文献类型：
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作者：
Cuypers L;Li G;Libin P;Piampongsant S;Vandamme AM;Theys K
针对不同病毒蛋白的全基因型直接作用抗病毒药物治疗是清除慢性感染患者丙型肝炎病毒（HCV）感染的最佳选择。然而，HCV基因组的多样性是抗病毒药物、疫苗和基因分型检测开发的主要障碍。在这项大规模分析中，绘制了全基因组多样性和选择压力图，重点关注对治疗、耐药性和耐药性测试重要的位置。对 1415 个全基因组序列的数据集进行了分析，其中包括来自洛斯阿拉莫斯数据库的基因型 1-6。在 44% 的全基因组位置中，至少一种基因型的共有氨基酸是不同的。关注所有基因型中共享相同共有氨基酸的位置发现，只有 15% 被定义为泛基因型高度保守（≥99% 氨基酸同一性），另外 24% 被定义为泛基因型保守（≥95%）。尽管其遗传多样性很大，但在所有基因型中，密码子位置很少被确定为正选择（0.23％–0.46％），并且主要发现处于负选择压力下，这表明主要是中性进化。对于 NS3、NS5A 和 NS5B，分别有 40% (6/15)、33% (3/9) 和 14% (2/14) 的耐药相关位置具有与耐药相关的氨基酸变异作为共识，可能阻碍治疗。例如，NS3 变体 80K 赋予对用于治疗 HCV1 感染患者的 simeprevir 的抗性，存在于 39.3% 的 HCV1a 毒株和 0.25% 的 HCV1b 毒株中。 NS5A 变体 28M 和 30S 已知与泛基因型药物 daclatasvir 耐药性相关，在相当比例的 HCV4 菌株中（10.7%）被发现。 NS5B 变体 556G 已知可赋予非核苷抑制剂达沙布韦耐药性，在 8.4% 的 HCV1b 菌株中观察到。鉴于 HCV 具有巨大的遗传多样性，用于耐药性检测的测序工作可能需要针对基因型或地理进行定制。
Treatment with pan-genotypic direct-acting antivirals, targeting different viral proteins, is the best option for clearing hepatitis C virus (HCV) infection in chronically infected patients. However, the diversity of the HCV genome is a major obstacle for the development of antiviral drugs, vaccines, and genotyping assays. In this large-scale analysis, genome-wide diversity and selective pressure was mapped, focusing on positions important for treatment, drug resistance, and resistance testing. A dataset of 1415 full-genome sequences, including genotypes 1–6 from the Los Alamos database, was analyzed. In 44% of all full-genome positions, the consensus amino acid was different for at least one genotype. Focusing on positions sharing the same consensus amino acid in all genotypes revealed that only 15% was defined as pan-genotypic highly conserved (≥99% amino acid identity) and an additional 24% as pan-genotypic conserved (≥95%). Despite its large genetic diversity, across all genotypes, codon positions were rarely identified to be positively selected (0.23%–0.46%) and predominantly found to be under negative selective pressure, suggesting mainly neutral evolution. For NS3, NS5A, and NS5B, respectively, 40% (6/15), 33% (3/9), and 14% (2/14) of the resistance-related positions harbored as consensus the amino acid variant related to resistance, potentially impeding treatment. For example, the NS3 variant 80K, conferring resistance to simeprevir used for treatment of HCV1 infected patients, was present in 39.3% of the HCV1a strains and 0.25% of HCV1b strains. Both NS5A variants 28M and 30S, known to be associated with resistance to the pan-genotypic drug daclatasvir, were found in a significant proportion of HCV4 strains (10.7%). NS5B variant 556G, known to confer resistance to non-nucleoside inhibitor dasabuvir, was observed in 8.4% of the HCV1b strains. Given the large HCV genetic diversity, sequencing efforts for resistance testing purposes may need to be genotype-specific or geographically tailored.