Background

Mutations in the core CVR region of hepatitis C virus (HCV) and polymorphisms of interleukin 28B (IL28B) are associated with progression toward liver disease and in response to therapy. In addition, interactions of the core protein with some cell interactors can be related to HCV liver damage.

Aim

This study aimed to evaluate the effect of core mutations as well as IL28B polymorphism on clinical features, sustained virological response (SVR) in 1a and 3a HCV genotypes amongst Iranian HCV infected patients, and the impact of mutations on core protein properties, antigenic properties, and interactions with HCV inhibitors, using several bioinformatics tools.

Methods

Seventy-nine Iranian patients infected with HCV genotypes 1a and 3a and diagnosed with chronic active hepatitis were examined. Plasma viral RNA was used to amplify and sequence the HCV Core gene; also, HCV viral load, molecular genotyping, and the liver enzymes were determined for all samples. The sequencing results were analyzed by several reliable bioinformatics tools to determine the physicochemical properties, B cell epitopes, post-modification changes, and secondary/tertiary structures; and evaluate the interactions with 4 drugs by docking method.

Result

There were some substitutions in core CVR related to ALT and AST enzymes that can lead to HCV advanced liver disease. The most prevalent mutation for 3a genotypes was a substitution in aa 162 (I to V) while we did not find any mutation in 1a responder group. Polymorphism of the rs8099917 showed that the majority of patients had TG heterozygous and carried CT genotype at the rs12979860. Analysis indicated several phosphorylation sits for core protein as well as two important disulfide bonds. Immunogenic prediction showed that core protein can strongly induce the immune system. Interaction analysis, using the docking method revealed two potential interactors (Vitronectin and SETD2).

Conclusion

Generally, mutations in all core CVR regions in all patients showed a relationship between such substitutions and higher liver enzymes that can result in advanced liver disease progression in HCV infected patients. Furthermore, immunoinformatics analysis determined the possible immunodominant regions to be considered in HCV vaccine designs. Furthermore, no association between SVR and IL28B polymorphism was shown. In silico analysis determined modification sites, structures, B-cell epitopes of core protein and interactions with several interactors can lead to persistent HCV infection in the cell and the progress of liver diseases.

中文翻译：

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IL28 基因型的影响和建模 HCV 核心蛋白对丙型肝炎治疗的相互作用。

背景

丙型肝炎病毒 (HCV) 核心 CVR 区域的突变和白介素 28B (IL28B) 的多态性与肝病进展和治疗反应相关。此外，核心蛋白与一些细胞相互作用因子的相互作用可能与 HCV 肝损伤有关。

目的

本研究旨在评估核心突变和 IL28B 多态性对伊朗 HCV 感染患者的临床特征、1a 和 3a HCV 基因型的持续病毒学应答 (SVR) 的影响，以及突变对核心蛋白特性、抗原特性、以及与 HCV 抑制剂的相互作用，使用几种生物信息学工具。

方法

对 79 名感染 HCV 基因型 1a 和 3a 并被诊断为慢性活动性肝炎的伊朗患者进行了检查。使用血浆病毒RNA对HCV Core基因进行扩增和测序；此外，还测定了所有样本的 HCV 病毒载量、分子基因分型和肝酶。测序结果通过几种可靠的生物信息学工具进行分析，以确定理化性质、B细胞表位、修饰后变化和二级/三级结构；并通过对接法评价与4种药物的相互作用。

结果

与 ALT 和 AST 酶相关的核心 CVR 中有一些替代，可导致 HCV 晚期肝病。3a 基因型最普遍的突变是 aa 162（I 到 V）中的替换，而我们在 1a 响应者组中没有发现任何突变。rs8099917 的多态性表明，大多数患者具有 TG 杂合子，并在 rs12979860 处携带 CT 基因型。分析表明核心蛋白和两个重要的二硫键有几个磷酸化。免疫原性预测表明，核心蛋白可以强烈诱导免疫系统。使用对接方法的相互作用分析揭示了两个潜在的相互作用物（玻连蛋白和 SETD2）。

结论

一般而言，所有患者的所有核心 CVR 区域的突变都显示出此类替代与更高的肝酶之间的关系，后者可导致 HCV 感染患者的晚期肝病进展。此外，免疫信息学分析确定了在 HCV 疫苗设计中要考虑的可能的免疫优势区域。此外，未显示 SVR 和 IL28B 多态性之间的关联。计算机分析确定的修饰位点、结构、核心蛋白的 B 细胞表位以及与几种相互作用物的相互作用可导致细胞中持续的 HCV 感染和肝脏疾病的进展。