Muñoz-Alía Miguel Ángel, Muller Claude P, Russell Stephen J
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Department of Infection and Immunity, Luxembourg Institute of Health, Esch-Sur-Alzette, Luxembourg.
J Virol. 2017 May 12;91(11). doi: 10.1128/JVI.00209-17. Print 2017 Jun 1.
The measles virus hemagglutinin (MeV-H) protein is the main target of protective neutralizing antibodies. Using a panel of monoclonal antibodies (MAbs) that recognize known major antigenic sites in MeV-H, we identified a D4 genotype variant that escapes neutralization by MAbs targeting the neutralizing epitope (NE) antigenic site. By site-directed mutagenesis, L249P was identified as the critical mutation disrupting the NE in this genotype D4 variant. Forty-two available D4 genotype gene sequences were subsequently analyzed and divided into 2 groups according to the presence or absence of the L249P MeV-H mutation. Further analysis of the MeV-N gene sequences of these 2 groups confirmed that they represent clearly definable, sequence-divergent D4 subgenotypes, which we named subgenotypes D4.1 and D4.2. The subgenotype D4.1 MeVs were isolated predominantly in Kenya and Ethiopia, whereas the MAb-resistant subgenotype D4.2 MeVs were isolated predominantly in France and Great Britain, countries with higher vaccine coverage rates. Interestingly, D4.2 subgenotype viruses showed a trend toward diminished susceptibility to neutralization by human sera pooled from approximately 60 to 80 North American donors. Escape from MAb neutralization may be a powerful epidemiological surveillance tool to monitor the evolution of new MeV subgenotypes. Measles virus is a paradigmatic RNA virus, as the antigenic composition of the vaccination has not needed to be updated since its discovery. The vaccine confers protection by inducing neutralizing antibodies that interfere with the function of the hemagglutinin protein. Viral strains are indistinguishable serologically, although characteristic nucleotide sequences differentiate 24 genotypes. In this work, we describe a distant evolutionary branch within genotype D4. Designated subgenotype D4.2, this virus is distinguishable by neutralization with vaccine-induced monoclonal antibodies that target the neutralizing epitope (NE). The subgenotype D4.2 viruses have a higher predominance in countries with intermediary levels of vaccine coverage. Our studies demonstrate that subgenotype D4.2 lacks epitopes associated with half of the known antigenic sites, which significantly impacts our understanding of measles virus evolution.
麻疹病毒血凝素（MeV-H）蛋白是保护性中和抗体的主要靶点。我们使用一组识别MeV-H中已知主要抗原位点的单克隆抗体（MAb），鉴定出一种D4基因型变体，该变体可逃避靶向中和表位（NE）抗原位点的MAb的中和作用。通过定点诱变，L249P被确定为破坏该D4基因型变体中NE的关键突变。随后对42个可用的D4基因型基因序列进行分析，并根据是否存在L249P MeV-H突变分为2组。对这两组的MeV-N基因序列进行进一步分析证实，它们代表了明确可定义的、序列不同的D4亚型，我们将其命名为D4.1和D4.2亚型。D4.1亚型的麻疹病毒主要在肯尼亚和埃塞俄比亚分离得到，而对MAb耐药的D4.2亚型麻疹病毒主要在疫苗接种覆盖率较高的法国和英国分离得到。有趣的是，D4.2亚型病毒对来自约60至80名北美捐赠者的混合人血清中和作用的敏感性呈降低趋势。逃避MAb中和作用可能是监测新的麻疹病毒亚型演变的有力流行病学监测工具。麻疹病毒是一种典型的RNA病毒，自发现以来，疫苗的抗原组成无需更新。该疫苗通过诱导干扰血凝素蛋白功能的中和抗体来提供保护。病毒株在血清学上无法区分，尽管特征性核苷酸序列可区分24种基因型。在这项工作中，我们描述了基因型D4内的一个远缘进化分支。这种被指定为D4.2亚型的病毒，可通过用靶向中和表位（NE）的疫苗诱导单克隆抗体进行中和来区分。D4.2亚型病毒在疫苗接种覆盖率中等的国家中占比更高。我们的研究表明，D4.2亚型缺乏与一半已知抗原位点相关的表位，这对我们理解麻疹病毒的进化有重大影响。
