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Evaluation of antiviral effect of type I, II, and III interferons on direct-acting antiviral-resistant hepatitis C virus
Antiviral Research ( IF 7.6 ) Pub Date : 2017-08-31 , DOI: 10.1016/j.antiviral.2017.08.017
Atsushi Hamana , Yuki Takahashi , Takuro Uchida , Makiya Nishikawa , Michio Imamura , Kazuaki Chayama , Yoshinobu Takakura

Treatment of hepatitis C virus (HCV) infection has greatly improved in the last 5 years because of the identification of direct-acting antivirals (DAAs). However, concerns exist regarding the emergence of drug resistance-associated substitutions (RASs). In this study, we evaluated the in vivo antiviral effect of three classes of interferons (IFNs), namely, types I, II, and III IFNs, on DAA-resistant HCVs. IFN-α2, IFN-γ, and IFN-λ1 were selected as typical types I, II, and III IFNs, respectively. Human hepatocyte-transplanted chimeric mice were infected with NS3-D168, NS5A-L31-, and NS5A-Y93-mutated HCVs, and the antiviral effect of IFN-α2, IFN-γ, and IFN-λ1 on these HCV RASs was examined. Chimeric mice infected with NS3- and NS5A-mutated HCVs were hydrodynamically injected with IFN-expressing plasmids to evaluate the antiviral effect of IFNs. Serum concentrations of IFNs were maintained for at least 42 days. We found that serum HCV level significantly decreased and serum and hepatic HCV levels reached below detection limit in 5/5 and 3/5 chimeric mice injected with IFN-γ- and IFN-λ1-expressing plasmids, respectively. The antiviral effect of IFN-α2 on DAA-resistant HCVs was weaker than that of IFN-γ and IFN-λ1. Serum ALT levels showed a small and transient increase in mice injected with the IFN-γ-expressing plasmid but not in mice injected with the IFN-λ1-expressing plasmid. However, no apparent histological damage was observed in the liver sections of mice injected with the IFN-γ-expressing plasmid. These results indicate that IFN-γ and IFN-λ1 are an attractive therapeutic option for treating infection caused by NS3- and NS5A-mutated HCV.



中文翻译:

评估I型,II型和III型干扰素对直接作用的抗病毒性丙型肝炎病毒的抗病毒作用

由于鉴定了直接作用抗病毒药(DAA),在过去5年中,丙型肝炎病毒(HCV)感染的治疗有了很大改善。但是,存在与耐药性取代(RASs)有关的担忧。在这项研究中,我们评估了三类干扰素(I,II和III型IFN)对DAA耐药性HCV的体内抗病毒作用。IFN-α 2,IFN-γ和IFN-λ 1分别选作典型类型I,II,和III干扰素。人肝细胞移植嵌合体小鼠感染NS3-D168,NS5A-L31-,和NS5A-Y93突变高保护价值,和IFN-α的抗病毒效果2,IFN-γ和IFN-λ 1在这些HCV RASs上进行了检查。将感染了NS3和NS5A突变的HCV的嵌合小鼠以流体动力学方式注射表达IFN的质粒,以评估IFN的抗病毒作用。IFNs的血清浓度维持至少42天。我们发现,血清HCV水平显著下降,血清和在5/5和3/5嵌合体小鼠低于检测限达到肝HCV水平与IFN-γ-和IFN-λ注射1 -表达质粒分别。IFN-α的抗病毒效果2上DAA耐高保护价值比IFN-γ和IFN-λ的较弱1。血清ALT水平在小鼠中显示一个小而短暂的增加注入与IFN-γ表达质粒而不是在小鼠与IFN-λ注射1表达质粒。然而,在注射有表达IFN-γ的质粒的小鼠的肝切片中未观察到明显的组织学损伤。这些结果表明,IFN-γ和IFN-λ 1是用于治疗由NS3-和NS5A-突变HCV感染有吸引力的治疗选择。

更新日期:2017-08-31
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