Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute associated with formation of large scale RNA structure in their genomic RNA. We developed novel methods to analyse and visualise genome-scale ordered RNA structure (GORS) predicted from the increasingly large datasets of complete genome sequences of HCV. Structurally conserved RNA secondary structure in coding regions of HCV localised exclusively to polyprotein ends (core, NS5B). Coding regions elsewhere were also intensely structured based on elevated minimum folding energy difference (MFED) values, but the actual stem-loop elements involved in genome folding were structurally entirely distinct, even between subtypes 1a and 1b. Dynamic remodelling was further evident from comparison of HCV strains in different host genetic background. Significantly higher MFED values, greater suppression of UpA dinucleotide frequencies and restricted diversification were found in subjects with the TT genotype of the rs12979860 SNP in the IFNL4 gene compared to the CC (non-expressing) allele. These structural and compositional associations with expression of interferon-λ4 were recapitulated on a larger scale by higher MFED values and greater UpA suppression of genotype 1 compared to genotype 3a, associated with previously reported HCV genotype-associated differences in hepatic interferon-stimulated gene induction. Associations between innate cellular responses with HCV structure and further evolutionary constraints represents an important new element in RNA virus evolution and the adaptive interplay between virus and host.

中文翻译：

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病毒亚型和宿主 IFNL4 基因型对丙型肝炎病毒基因组中大规模 RNA 结构形成的影响

丙型肝炎病毒 (HCV) 建立持续感染并诱发进行性肝病的潜在机制仍然知之甚少。HCV 是几种能够在具有免疫活性的脊椎动物宿主中建立持久性的正链 RNA 病毒之一，这种属性与在其基因组 RNA 中形成大规模 RNA 结构有关。我们开发了新的方法来分析和可视化从越来越大的 HCV 完整基因组序列数据集预测的基因组规模有序 RNA 结构 (GORS)。HCV 编码区中结构保守的 RNA 二级结构，仅位于多蛋白末端（核心，NS5B）。其他地方的编码区域也基于升高的最小折叠能量差 (MFED) 值进行了密集结构化，但是参与基因组折叠的实际茎环元件在结构上完全不同，即使在亚型 1a 和 1b 之间也是如此。通过比较不同宿主遗传背景下的 HCV 菌株，动态重塑更加明显。与 CC（不表达）等位基因相比，在 IFNL4 基因中具有 rs12979860 SNP TT 基因型的受试者中发现了显着更高的 MFED 值、对 UpA 二核苷酸频率的更大抑制和有限的多样化。这些与干扰素-λ4 表达的结构和组成关联通过更高的 MFED 值和基因型 1 与基因型 3a 相比更大的 UpA 抑制在更大范围内重现，这与先前报道的肝干扰素刺激基因诱导的 HCV 基因型相关差异相关。