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血液透析终末期肾病患者丙型肝炎病毒的分子特征。

Molecular characterization of hepatitis C virus in end-stage renal disease patients under hemodialysis.

机构信息

Laboratório de Hepatologia Molecular Aplicada (LHeMA), Departamento de Gastroenterologia, Unidade de Hepatologia, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil.

Instituto Butantan, Laboratório de Parasitologia, São Paulo, Brazil.

出版信息

J Med Virol. 2018 Mar;90(3):537-544. doi: 10.1002/jmv.24976. Epub 2017 Nov 16.

DOI:10.1002/jmv.24976
PMID:29064576
Abstract

New direct-acting antiviral (DAA) agents are in development or already approved for the treatment of chronic hepatitis C virus (HCV) infection. The effectiveness of these drugs is related to the previous existence of resistant variants. Certain clinical conditions can allow changes in immunological characteristics of the host and even modify genetic features of viral populations. The aim of this study was to perform HCV molecular characterization from samples of end-stage renal disease patients on hemodialysis (ESRD-HD). Nested PCR and Sanger sequencing were used to obtain genetic information from the NS5B partial region of a cohort composed by 86 treatment-naïve patients. Genomic sequences from the Los Alamos databank were employed for comparative analysis. Bioinformatics methodologies such as phylogenetic reconstructions, informational entropy, and mutation analysis were used to analyze datasets separated by geographical location, HCV genotype, and renal function status. ESRD-HD patients presented HCV genotypes 1a (n = 18), 1b (n = 16), 2a (n = 2), 2b (n = 2), and 3a (n = 4). Control subjects were infected with genotypes 1a (n = 11), 1b (n = 21), 2b (n = 4), and 3a (n = 8). Dataset phylogenetic reconstruction separated HCV subtype 1a into two distinct clades. The entropy analysis from the ESRD-HD group revealed two amino acid positions related to an epitope for cytotoxic T lymphocytes and T helper cells. Genotype 1a was found to be more diverse than subtype 1b. Also, genotype 1a ERSD-HD patients had a higher mean of amino acids changes in comparison to control group patients. The identification of specific mutations on epitopes and high genetic diversity within the NS5B HCV partial protein in hemodialysis patients can relate to host immunological features and geographical distribution patterns. This genetic diversity can affect directly the new DAA's resistance mechanisms.

摘要

新的直接作用抗病毒 (DAA) 药物正在开发或已被批准用于治疗慢性丙型肝炎病毒 (HCV) 感染。这些药物的有效性与先前存在的耐药变异有关。某些临床情况可以改变宿主的免疫特征,甚至改变病毒群体的遗传特征。本研究旨在从血液透析 (ESRD-HD) 的终末期肾病患者的样本中进行 HCV 分子特征分析。巢式 PCR 和 Sanger 测序用于从由 86 名未经治疗的患者组成的队列的 NS5B 部分区域获得遗传信息。来自洛斯阿拉莫斯数据库的基因组序列用于比较分析。生物信息学方法,如系统发育重建、信息熵和突变分析,用于分析按地理位置、HCV 基因型和肾功能状况分开的数据集。ESRD-HD 患者的 HCV 基因型为 1a(n=18)、1b(n=16)、2a(n=2)、2b(n=2)和 3a(n=4)。对照组患者感染基因型 1a(n=11)、1b(n=21)、2b(n=4)和 3a(n=8)。数据集系统发育重建将 HCV 亚型 1a 分为两个不同的分支。ESRD-HD 组的熵分析显示了与细胞毒性 T 淋巴细胞和辅助性 T 细胞表位相关的两个氨基酸位置。发现基因型 1a 比亚型 1b 更具多样性。此外,基因型 1a ESRD-HD 患者的氨基酸变化平均值高于对照组患者。在血液透析患者的 HCV NS5B 部分蛋白中,鉴定出特定的表位突变和高遗传多样性可能与宿主免疫特征和地理分布模式有关。这种遗传多样性可能直接影响新的 DAA 的耐药机制。

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