Antibodies to the Buried N Terminus of Rhinovirus VP4 Exhibit Cross-Serotypic Neutralization
Antibodies to the Buried N Terminus of Rhinovirus VP4 Exhibit Cross-Serotypic Neutralization
复制标题
DOI：
10.1128/jvi.00557-09
复制
发表时间：
2009-07-15
影响因子：
5.4
通讯作者：
Smith, Thomas J.
中科院分区：
文献类型：
--
作者：
Katpally, Umesh;Fu, Tong-Ming;Smith, Thomas J.
人类鼻病毒（HRV）有100多种血清型，这一事实阻碍了普通感冒疫苗的开发。我们之前已经证明，HRV14衣壳是动态的，可以瞬时显示病毒蛋白1 （VP1）和VP4的隐埋N端。在这里，进一步的证据为这种“呼吸”现象提出，使用抗体的几个肽代表VP4的N端。抗体与完整的HRV14病毒粒子形成稳定的复合物，并中和感染性。由于VP4的这一区域在所有鼻病毒中高度保守，这些抗VP4抗体的抗病毒活性是跨血清型的。抗体以与呼吸行为一致的温度和时间依赖性方式抑制HRV16的传染性。针对30残基肽的单克隆和多克隆抗体不与短于24残基的肽反应，这表明这些肽采用高度依赖于肽长度的三维构象。此外，有证据表明VP4的N端在从衣壳挤出时相互作用。VP4的Ser5Cys突变产生一种感染性病毒，当病毒在室温（而不是4℃）下孵育时，该病毒在VP4中形成半胱氨酸交联。所有VP4都参与这种交联过程的事实强烈表明VP4在挤压时形成特异性低聚物。总之，这些结果表明，开发一种针对HRV的泛血清型肽疫苗是可能的，但其设计可能需要有关暴露末端的寡聚结构的细节。
Development of a vaccine for the common cold has been thwarted by the fact that there are more than 100 serotypes of human rhinovirus (HRV). We previously demonstrated that the HRV14 capsid is dynamic and transiently displays the buried N termini of viral protein 1 (VP1) and VP4. Here, further evidence for this "breathing" phenomenon is presented, using antibodies to several peptides representing the N terminus of VP4. The antibodies form stable complexes with intact HRV14 virions and neutralize infectivity. Since this region of VP4 is highly conserved among all of the rhinoviruses, antiviral activity by these anti-VP4 antibodies is cross-serotypic. The antibodies inhibit HRV16 infectivity in a temperature- and time-dependent manner consistent with the breathing behavior. Monoclonal and polyclonal antibodies raised against the 30-residue peptide do not react with peptides shorter than 24 residues, suggesting that these peptides are adopting three-dimensional conformations that are highly dependent upon the length of the peptide. Furthermore, there is evidence that the N termini of VP4 are interacting with each other upon extrusion from the capsid. A Ser5Cys mutation in VP4 yields an infectious virus that forms cysteine cross-links in VP4 when the virus is incubated at room temperature but not at 4 degrees C. The fact that all of the VP4s are involved in this cross-linking process strongly suggests that VP4 forms specific oligomers upon extrusion. Together these results suggest that it may be possible to develop a pan-serotypic peptide vaccine to HRV, but its design will likely require details about the oligomeric structure of the exposed termini.