Laboratorio di Microbiologia e Virologia, Università Vita-Salute San Raffaele, Milano, Italy.
Antiviral Res. 2012 Oct;96(1):82-9. doi: 10.1016/j.antiviral.2012.07.013. Epub 2012 Aug 7.
The suggested HCV escape mechanism consisting in the elicitation of antibody (Ab) subpopulations interfering with the neutralizing activity of other Abs has recently been questioned. In particular, it was originally reported that Abs directed against the 436-447 region (epitope II) of HCV/E2 glycoprotein may interfere with the neutralizing Abs directed against the 412-423 region (epitope I) involved in the binding to CD81. In this paper, we investigate on the molecular features of this phenomenon describing an anti-HCV/E2 monoclonal Ab (mAb) (e509) endowed with a weak neutralizing activity, and whose epitope is centered on epitope II. Interestingly, e509 influenced the potent neutralizing activity of AP33, one of the best characterized anti-HCV/E2 mAb, whereas it did not show any interfering activity against two other broadly neutralizing mAbs (e20 and e137), whose epitopes partially overlap with that of e509 and which possibly displace it from the antigen. These data may give a possible clue to interpret the conflicting studies published to date on the mechanism of interference, suggesting the existence of at least two groups of broadly neutralizing anti-HCV/E2 Abs: (i) those whose epitope is focused on the 412-423 CD81-binding region and whose activity may be hampered by other Abs directed against the 436-447 region, and (ii) those directed against CD81-binding regions but whose epitope contains also residues within the 436-447 region recognized by interfering mAbs, thus competing with them for binding. The conflicting results of previous studies may therefore depend on the relative amount of each of these two populations in the polyclonal preparations used. Overall, a better comprehension of this phenomenon may be of importance in the set up of novel mAb-based anti-HCV therapeutic strategies.
最近，人们对 HCV 逃逸机制提出了质疑，该机制认为抗体（Ab）亚群的诱导会干扰其他 Ab 的中和活性。特别是，最初有报道称，针对 HCV/E2 糖蛋白 436-447 区域（表位 II）的 Ab 可能会干扰针对 412-423 区域（表位 I）的中和 Ab，该区域参与与 CD81 的结合。在本文中，我们研究了这种现象的分子特征，描述了一种具有弱中和活性的抗 HCV/E2 单克隆 Ab（mAb）（e509），其表位集中在表位 II 上。有趣的是，e509 影响了一种最具特征的抗 HCV/E2 mAb（AP33）的强大中和活性，而它对另外两种广泛中和的 mAb（e20 和 e137）没有表现出任何干扰活性，这两种 mAb 的表位与 e509 部分重叠，可能将其从抗原上置换下来。这些数据可能为解释迄今为止发表的关于干扰机制的相互矛盾的研究提供了一个可能的线索，表明至少存在两类广泛中和的抗 HCV/E2 Abs：（i）那些表位集中在 412-423 CD81 结合区域的 Abs，其活性可能会受到针对 436-447 区域的其他 Ab 的阻碍，以及（ii）那些针对 CD81 结合区域的 Abs，但它们的表位也包含被干扰 mAb 识别的 436-447 区域的残基，因此与它们竞争结合。因此，以前研究的相互矛盾的结果可能取决于在使用的多克隆制剂中这两种群体的相对数量。总体而言，更好地理解这一现象可能对建立新的基于 mAb 的抗 HCV 治疗策略很重要。
