Division of Infectious Diseases, Ospedale San Raffaele, 20132 Milan, Italy.
Vita-Salute University, 20132 Milan, Italy.
Viruses. 2019 Feb 11;11(2):148. doi: 10.3390/v11020148.
Little is known about the frequency or geographic distributions of naturally occurring resistance-associated substitutions (RASs) in the nonstructural protein 5A (NS5A) domain of hepatitis-C virus (HCV) genotype-3 (GT-3) different subtypes. We investigated naturally occurring GT-3 RASs that confer resistance to NS5A inhibitors.
From a publicly accessible database, we retrieved 58 complete GT-3 genomes and an additional 731 worldwide NS5A sequences from patients infected with GT-3 that were naive to direct-acting antiviral treatment.
We performed a phylogenetic analysis of NS5A domains in complete HCV genomes to determine more precisely HCV-GT-3 subtypes, based on commonly used target regions (e.g., 5'untranslated region and NS5B partial domain). Among 789 NS5A sequences, GT-3nonA subtypes were more prevalent in Asia than in other geographic regions (P<0.0001). The A30K RAS was detected more frequently in HCV GT3nonA (84.6%) than in GT-3A subtypes (0.8%), and the amino acid change was polymorphic in isolates from Asia.
These results provided information on the accuracy of HCV-3 subtyping with a phylogenetic analysis of the NS5A domain with data from the Los Alamos HCV genome database. This information and the worldwide geographic distribution of RASs according to HCV GT-3 subtypes are crucial steps in meeting the challenges of treating HCV GT-3.
关于丙型肝炎病毒 (HCV) 基因型 3 (GT-3) 不同亚型中非结构蛋白 5A (NS5A) 区中天然存在的耐药相关取代 (RAS) 的频率或地理分布情况知之甚少。我们研究了导致 NS5A 抑制剂耐药的天然存在的 GT-3 RAS。
我们从一个公开可访问的数据库中检索了 58 个完整的 GT-3 基因组和另外 731 个来自未接受直接作用抗病毒治疗的 GT-3 感染患者的全球 NS5A 序列。
我们对完整 HCV 基因组中的 NS5A 结构域进行了系统发育分析，以便根据常用的靶区（例如 5'非翻译区和 NS5B 部分结构域）更准确地确定 HCV-GT-3 亚型。在 789 个 NS5A 序列中，GT-3nonA 亚型在亚洲比在其他地理区域更为流行 (P<0.0001)。A30K RAS 在 HCV GT3nonA 中比在 GT-3A 亚型中更常见 (84.6%对 0.8%)，并且在亚洲分离株中氨基酸变化是多态性的。
这些结果提供了有关使用 NS5A 结构域的系统发育分析对 HCV-3 亚型进行准确分型的信息，以及根据 HCV GT-3 亚型的全球 RAS 地理分布情况。这些信息和 RAS 是应对 HCV GT-3 治疗挑战的关键步骤。
