Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity.
Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity.
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DOI：
10.1002/hep.28705
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发表时间：
2016-12
期刊：
影响因子：
13.5
通讯作者：
Bukh, Jens
中科院分区：
文献类型：
--
作者：
Prentoe, Jannick;Velazquez-Moctezuma, Rodrigo;Foung, Steven K. H.;Law, Mansun;Bukh, Jens
每年有3-4百万新的丙型肝炎病毒（HCV）感染。HCV包膜蛋白E1和E2广泛的基因型序列多样性以及E2的高变区1 （HVR1）对重要表位的屏蔽被认为是开发具有普遍保护作用的HCV疫苗的主要障碍。使用表达分离株H77（基因型1a）、J6 （2a）或S52 （3a）的E1/E2复合体的培养病毒，无论是否含有HVR1，我们在体外测试了HVR1介导的中和阻断，这些中和阻断针对不同E1、E2和E1/E2表位的12种特性良好的人单克隆抗体（hmab）。令人惊讶的是，hvr1介导的保护作用在S52中最大，其次是J6，然后是H77。HCV下拉实验表明，这种现象是由表位屏蔽引起的。此外，通过HMAb结合和HCV中和滴度的回归分析，我们发现HVR1缺失的病毒与HVR1有很强的相关性，而与保留HVR1的亲本病毒没有很强的相关性。亲本病毒对hmab抗体AR2A、AR3A、AR4A、AR5A、HC84.26和HC33.4的基因型间中和敏感性差异很大（>和>的ic50值差异为24- 130倍）。然而，除AR5A外，与相应的hvr1缺失病毒相比，这些差异减少到不到6.0倍。重要的是，在一组基因型为1a、2a、2b、3a、5a和6a的HVR1缺失病毒中也证实了这种简化的中和敏感性模式，尽管除了AR4A外，所有hmab都有异常值。最后，HCV E2中独特的氨基酸残基可以解释AR5A和HC84.26测试病例中的异常值。结论：HVR1通过屏蔽多种意想不到的交叉基因型保守的E1/E2表位，增加了HCV中和的复杂性。因此，hvr1缺失抗原可能是一种更好的HCV疫苗免疫原。
There are 3-4 million new hepatitis C virus (HCV) infections yearly. The extensive inter-genotypic sequence diversity of envelope proteins E1 and E2 of HCV and shielding of important epitopes by hypervariable region 1 (HVR1) of E2 are believed to be major hindrances to developing universally protective HCV vaccines. Using cultured viruses expressing the E1/E2 complex of isolates H77 (genotype 1a), J6 (2a), or S52 (3a), with and without HVR1, we tested HVR1-mediated neutralization occlusion in vitro against a panel of 12 well-characterized human monoclonal antibodies (HMAbs) targeting diverse E1, E2, and E1/E2 epitopes. Surprisingly, HVR1-mediated protection was greatest for S52, followed by J6 and then H77. HCV pulldown experiments showed that this phenomenon was caused by epitope shielding. Moreover, by regression analysis of HMAb binding and neutralization titer of HCV we found a strong correlation for HVR1-deleted viruses, but not for parental viruses retaining HVR1. The inter-genotype neutralization sensitivity of the parental viruses to HMAbs AR2A, AR3A, AR4A, AR5A, HC84.26, and HC33.4 varied greatly (>24- to >130-fold differences in IC50-values). However, except for AR5A, these differences decreased to less than 6.0-fold when comparing the corresponding HVR1-deleted viruses. Importantly, this simplified pattern of neutralization sensitivity in the absence of HVR1 was also demonstrated in a panel of HVR1-deleted viruses of genotypes 1a, 2a, 2b, 3a, 5a, and 6a, although for all HMAbs, except AR4A, an outlier was observed. Finally, unique amino acid residues in HCV E2 could explain these outliers in the tested cases of AR5A and HC84.26. Conclusion: HVR1 adds complexity to HCV neutralization by shielding a diverse array of unexpectedly cross-genotype-conserved E1/E2 epitopes. Thus, an HVR1-deleted antigen could be a better HCV vaccine immunogen.
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