Mapping the genomic diversity of HCV subtypes 1a and 1b: Implications of structural and immunological constraints for vaccine and drug development.
Mapping the genomic diversity of HCV subtypes 1a and 1b: Implications of structural and immunological constraints for vaccine and drug development.
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绘制 HCV 亚型 1a 和 1b 的基因组多样性：结构和免疫学限制对疫苗和药物开发的影响。
DOI：
10.1093/ve/vew024
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发表时间：
2016-07
期刊：
影响因子：
5.3
通讯作者：
Theys K
中科院分区：
文献类型：
--
作者：
Cuypers L;Li G;Neumann-Haefelin C;Piampongsant S;Libin P;Van Laethem K;Vandamme AM;Theys K
尽管丙型肝炎（HCV）治疗取得了重大进展，但全球病毒根除仍然是一个挑战。在结构和免疫学限制的背景下，其基因组多样性的深入图谱可能有助于泛基因型抗病毒药物和预防性疫苗的设计。对于此类分析，仅可获得高度流行的HCV基因型（GT）1a和1b的广泛信息。使用从洛斯阿拉莫斯数据库获得的647个GT1a和408个GT1b全基因组序列，我们发现分别有3%和82%的密码子位置处于正选择压力和负选择压力下，这表明变异主要是由于随机遗传漂变而积累的。保守性与结构化RNA和二级蛋白质结构之间的关联证实了结构元件在核苷酸和氨基酸水平上的重要作用。值得注意的是，HCV GT1a中的CD8+ T细胞表位明显更加保守，同时含有更多的正选择位点。类似地，CD4+ T细胞表位在两种HCV亚型中显著更保守，但在GT1b中的正选择压力较小，而在GT1a中的负选择压力较大。相比之下，两种亚型中的B细胞表位保守性较低，并且在较不严格的阴性选择下。这些发现反对免疫选择压力作为宿主间多样化进化的主要力量。尽管其变异性很高，但HCV受到严格的进化限制，很可能是为了在复制周期中保持其基因和蛋白质的功能。这些对于疫苗和药物设计来说是令人鼓舞的发现，可以考虑这些新建立的遗传多样性概况。
Despite significant progress in hepatitis C (HCV) treatment, global viral eradication remains a challenge. An in-depth map of its genome diversity within the context of structural and immunological constraints could contribute to the design of pan-genotypic antivirals and preventive vaccines. For such analyses, extensive information is only available for the highly prevalent HCV genotypes (GT) 1a and 1b. Using 647 GT1a and 408 GT1b full-genome sequences obtained from the Los Alamos database, we found that respectively 3 per cent and 82 per cent of all codon positions are under positive and negative selective pressure, suggesting variation mainly accumulates due to random genetic drift. An association between conservation and both structured RNA and secondary protein structures confirmed the important role of structural elements at nucleotide and at amino acid level. Remarkably, CD8+ T-cell epitopes in HCV GT1a were significantly more conserved, while at the same time containing more sites under positive selection. Similarly, CD4+ T-cell epitopes were significantly more conserved in both HCV subtypes, but under less positive selective pressure in GT1b and more negative selective pressure in GT1a. In contrast, B-cell epitopes in both subtypes were less conserved and under less stringent negative selection. These findings argue against immune selective pressure as the main force of between-host diversifying evolution. Despite its high variability, HCV is under strict evolutionary constraints, most probably to keep its genes and proteins functional during the replication cycle. These are encouraging findings for vaccine and drug design, which could consider these newly established genetic diversity profiles.
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影响因子：
5.2
作者：
Ito M;Kusunoki H;Mizuochi T
通讯作者：
Mizuochi T
影响因子：
29.4
作者：
Franco, Sandra;Tural, Cristina;Angel Martinez, Miguel
通讯作者：
Angel Martinez, Miguel
影响因子：
5.7
作者：
Berry, Katherine E.;Waghray, Shruti;Doudna, Jennifer A.
通讯作者：
Doudna, Jennifer A.
影响因子：
4.8
作者：
Costantino A;Spada E;Equestre M;Bruni R;Tritarelli E;Coppola N;Sagnelli C;Sagnelli E;Ciccaglione AR
通讯作者：
Ciccaglione AR
影响因子：
6.4
作者：
Blackard, JT;Yang, YJ;Chung, RT
通讯作者：
Chung, RT