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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Impact of Viral Amino Acid Substitutions and Host Interleukin-28B Polymorphism on Replication and Susceptibility to Interferon of Hepatitis C Virus
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Impact of Viral Amino Acid Substitutions and Host Interleukin-28B Polymorphism on Replication and Susceptibility to Interferon of Hepatitis C Virus

机译：病毒氨基酸取代和宿主白细胞介素28B多态性对丙型肝炎病毒复制和易感性的影响。

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摘要

Amino acid (aa) substitutions of core 70 and 91 and in the NS5A (nonstructural protein 5A) interferon sensitivity determining region (ISDR) as well as genetic polymorphisms in the host interleukin-28B (IL28B) locus affect the outcome of interferon (IFN)-based therapies for patients with chronic hepatitis C. The combination of these factors and the quasi-species nature of the virus complicate understanding of the underlying mechanism. Using infectious hepatitis C virus (HCV) genotype 1b clone HCV-KT9, we introduced substitutions at both core aa70 (Arg to Gln) and aa91 (Leu to Met). We also introduced four and nine ISDR aa substitutions into core mutant HCV-KT9. Using human hepatocyte chimeric mice with different IL28B genotypes, we examined the infectivity, replication ability, and susceptibility to IFN of these clones. Although aa substitutions in the ISDR significantly impaired infectivity and replication ability of the virus, core aa70 and 91 substitutions did not. The effect of IFN treatment was similar in core wild-type and mutant viruses. Interestingly, virus titer was significantly higher in mice with the favorable IL28B allele (rs8099917 TT and rsl2979860 CC) in the transplanted hepatocytes than in mice with he-patocytes from rs8099917 TG and rsl2979860 TT donors (P < 0.001). However, the effect of IFN was significandy greater, and intrahepatic expression levels of IFN-stimulated genes were significantly higher in mice with the favorable IL28B allele. Conclusion: Our data suggest that HCV replication levels and response to IFN are affected by human hepatocyte IL28B single-nucleotide polymorphism genotype and mutations in the ISDR. The mechanism underlying the clinically observed association of wild-type core protein in eradication-favorable host cells should be investigated further.
机译：核心70和91以及NS5A（非结构蛋白5A）干扰素敏感性决定区（ISDR）中的氨基酸（aa）取代以及宿主白介素28B（IL28B）基因座中的遗传多态性影响干扰素（IFN）的结果慢性丙型肝炎患者的常规治疗。这些因素与病毒的准种性质的结合使人们对潜在机制的理解更加复杂。使用传染性丙型肝炎病毒（HCV）基因型1b克隆HCV-KT9，我们在核心aa70（从Arg到Gln）和aa91（从Leu到Met）的核心处引入了替代。我们还向核心突变体HCV-KT9中引入了四个和九个ISDR氨基酸置换。使用具有不同IL28B基因型的人肝细胞嵌合小鼠，我们检查了这些克隆的感染性，复制能力和对IFN的敏感性。尽管ISDR中的aa取代显着削弱了病毒的感染性和复制能力，但核心aa70和91取代却没有。在核心野生型和突变型病毒中，IFN处理的效果相似。有趣的是，在移植的肝细胞中具有有利的IL28B等位基因（rs8099917 TT和rs1297960 CC）的小鼠中，病毒滴度显着高于具有rs8099917 TG和rs1297960 TT供体的肝细胞的小鼠中的病毒滴度（P <0.001）。然而，在具有有利的IL28B等位基因的小鼠中，IFN的作用明显更大，并且IFN刺激基因的肝内表达水平明显更高。结论：我们的数据表明HCV复制水平和对IFN的反应受人肝细胞IL28B单核苷酸多态性基因型和ISDR突变的影响。临床上观察到的有利于根除的宿主细胞中野生型核心蛋白缔合的潜在机制应进一步研究。

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