Tian Xingui, Qiu Hongling, Zhou Zhichao, Wang Shouli, Fan Ye, Li Xiao, Chu Ruiai, Li Haitao, Zhou Rong, Wang Hui
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
Key Laboratory of Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
J Virol. 2018 Jan 2;92(2). doi: 10.1128/JVI.01643-17. Print 2018 Jan 15.
Human adenovirus type 4 (HAdV-4) is an epidemic virus that contributes to serious acute respiratory disease (ARD) in both pediatric and adult patients. However, no licensed drug or vaccine is currently available to the civilian population. The identification of neutralizing epitopes of HAdV-4 should allow the development of a novel antiviral vaccine and a novel gene transfer vector, and an effective neutralizing monoclonal antibody (MAb) will be useful in developing appropriate antiviral drugs. In this study, we report that MAb MN4b shows strong neutralizing activity against HAdV-4. MN4b recognizes a conformational epitope (418AGSEK422) within hypervariable region 7 (HVR7). Mutations within this site permitted HAdV-4 mutants to escape neutralization by MN4b and to resist neutralization by animal and human anti-HAdV-4 sera. A recombinant virus, rAd3-A4R7-1, containing the identified neutralizing epitope in the HVR7 region of HAdV-3 hexon, successfully induced antiserum that inhibited HAdV-4 infection. These results indicate that a small surface loop of HAdV-4 hexon is a critical neutralization epitope for this virus. The generation of MN4b and the identification of this neutralizing epitope may be useful in developing therapeutic treatment, a subunit vaccine, and a novel vector that can escape preexisting neutralization for HAdV-4. Neutralizing antibodies are considered good tools for the prevention of human adenovirus type 4 (HAdV-4) infections. The identification of the epitopes recognized by such neutralizing antibodies is important for the generation of recombinant antiviral vaccines. However, until now, no neutralizing epitope has been reported for HAdV-4. Here, we developed a serotype-specific neutralizing MAb directed against HAdV-4, MN4b. We provide evidence that MN4b recognizes a conformational epitope within HVR7 of HAdV-4 hexon. Antisera generated to this conformational epitope displayed on HAdV-3 hexon inhibited infection of AD293 cells by HAdV-4. Our findings are very important for the development of therapeutic treatment, a subunit vaccine, and a novel vector for HAdV-4.
人4型腺病毒（HAdV-4）是一种流行性病毒，可导致儿童和成人患者患上严重的急性呼吸道疾病（ARD）。然而，目前尚无面向普通民众的获批药物或疫苗。鉴定HAdV-4的中和表位应有助于开发新型抗病毒疫苗和新型基因转移载体，并且有效的中和单克隆抗体（MAb）将有助于开发合适的抗病毒药物。在本研究中，我们报告MAb MN4b对HAdV-4表现出强大的中和活性。MN4b识别高变区7（HVR7）内的一个构象表位（418AGSEK422）。该位点的突变使HAdV-4突变体能够逃避MN4b的中和作用，并抵抗动物和人抗HAdV-4血清的中和作用。一种重组病毒rAd3-A4R7-1，在HAdV-3六邻体的HVR7区域含有已鉴定的中和表位，成功诱导出抑制HAdV-4感染的抗血清。这些结果表明，HAdV-4六邻体的一个小表面环是该病毒的关键中和表位。MN4b的产生以及该中和表位的鉴定可能有助于开发治疗方法、亚单位疫苗以及一种能够逃避针对HAdV-4的预先存在的中和作用的新型载体。中和抗体被认为是预防人4型腺病毒（HAdV-4）感染的良好工具。鉴定此类中和抗体识别的表位对于产生重组抗病毒疫苗很重要。然而，迄今为止，尚未报道HAdV-4的中和表位。在此，我们开发了一种针对HAdV-4的血清型特异性中和MAb，MN4b。我们提供的证据表明，MN4b识别HAdV-4六邻体HVR7内的一个构象表位。针对展示在HAdV-3六邻体上的该构象表位产生的抗血清抑制了HAdV-4对AD293细胞的感染。我们的发现对于开发针对HAdV-4的治疗方法、亚单位疫苗和新型载体非常重要。
