Cryptic properties of a cluster of dominant flavivirus cross-reactive antigenic sites
Cryptic properties of a cluster of dominant flavivirus cross-reactive antigenic sites
复制标题
DOI：
10.1128/jvi.00080-06
复制
发表时间：
2006-10-01
影响因子：
5.4
通讯作者：
Heinz, Franz X.
中科院分区：
文献类型：
--
作者：
Stiasny, Karin;Kiermayr, Stefan;Heinz, Franz X.
一些黄病毒是人类的重要病原体，包括黄热病、登革热、西尼罗河病毒、日本脑炎和壁虱传播脑炎(TBE)病毒。感染这些病毒或对其中任何一种进行免疫会诱导一组抗体，这些抗体与黄病毒有广泛的交叉反应，但不表现出明显的交叉中和作用。然而，这些抗体可以有效地与主要包膜蛋白(E)结合，而E蛋白是中和抗体和保护性抗体的主要靶点，因为它具有受体结合和膜融合功能。这一现象的结构性基础仍不明朗。在我们对TBE病毒的研究中，我们提供了证据，证明这种交叉反应抗体是针对一组表位的，这些表位部分封闭在感染性病毒粒子表面E蛋白的笼状组装中，并涉及-但不限于-高度保守的内部融合肽环的氨基酸。病毒的解体导致这些表位的可及性增加，允许交叉反应的抗体以强烈增加的亲和力结合。因此，这些位点在感染性病毒粒子背景下的神秘性质可以解释为什么观察到的广谱交叉反应抗体缺乏有效的中和活性，尽管它们对E蛋白中一个重要的功能结构元件具有特异性。
A number of flaviviruses are important human pathogens, including yellow fever, dengue, West Nile, Japanese encephalitis, and tick-borne encephalitis (TBE) viruses. Infection with or immunization against any of these viruses induces a subset of antibodies that are broadly flavivirus cross-reactive but do not exhibit significant cross-neutralization. Nevertheless, these antibodies can efficiently bind to the major envelope protein (E), which is the main target of neutralizing and protective antibodies because of its receptor-binding and membrane fusion functions. The structural basis for this phenomenon is still unclear. In our studies with TBE virus, we have provided evidence that such cross-reactive antibodies are specific for a cluster of epitopes that are partially occluded in the cage-like assembly of E proteins at the surfaces of infectious virions and involve-but are not restricted to-amino acids of the highly conserved internal fusion peptide loop. Virus disintegration leads to increased accessibility of these epitopes, allowing the cross-reactive antibodies to bind with strongly increased avidity. The cryptic properties of these sites in the context of infectious virions can thus provide an explanation for the observed lack of efficient neutralizing activity of broadly cross-reactive antibodies, despite their specificity for a functionally important structural element in the E protein.