In vivo role of complement-interacting domains of herpes simplex virus type 1 glycoprotein gC.
In vivo role of complement-interacting domains of herpes simplex virus type 1 glycoprotein gC.
复制标题
单纯疱疹病毒1型糖蛋白GC的补体相互作用结构域的体内作用。
DOI：
10.1084/jem.190.11.1637
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发表时间：
1999-12-06
影响因子：
15.3
通讯作者：
Friedman, H M
中科院分区：
文献类型：
--
作者：
Lubinski, J;Wang, L;Mastellos, D;Sahu, A;Lambris, J D;Friedman, H M
免疫逃避对于建立持续或反复感染的病毒的生存至关重要。然而，在分子水平上，人们对病毒如何在体内逃避免疫攻击知之甚少。单纯疱疹病毒(HSV)-1糖蛋白GC有两个参与调节补体激活的结构域：一个与C3结合，另一个是阻断C5和备解素(P)与C3的结合所必需的。为了评估这些区域在体内的重要性，构建了缺乏一个或两个GC结构域的HSV-1GC突变病毒，并在小鼠感染模型中进行了研究。补体调节的每个GC区域都有助于毒力；然而，C3结合结构域要重要得多，因为缺少该结构域的病毒比没有C5/P抑制结构域的病毒毒力低得多，而且与缺乏这两个结构域的病毒一样弱。对C3基因敲除小鼠和C3重组小鼠的研究证实，GC结构域是补体激活的抑制因子，这是突变型病毒和野生型病毒毒力差异50倍的原因。我们的结论是，GC上的C3结合域是免疫逃避的主要贡献者，这个位点在分子水平上解释了为什么野生型病毒抵抗补体攻击。
Immune evasion is critical for survival of viruses that establish persistent or recurrent infections. However, at the molecular level, little is known about how viruses evade immune attack in vivo. Herpes simplex virus (HSV)-1 glycoprotein gC has two domains that are involved in modulating complement activation; one binds C3, and the other is required for blocking C5 and properdin (P) binding to C3. To evaluate the importance of these regions in vivo, HSV-1 gC mutant viruses were constructed that lacked one or both gC domains and studied in a murine model of infection. Each gC region of complement regulation contributed to virulence; however, the C3 binding domain was far more important, as virus lacking this domain was much less virulent than virus lacking the C5/P inhibitory domain and was as attenuated as virus lacking both domains. Studies in C3 knockout mice and mice reconstituted with C3 confirmed that the gC domains are inhibitors of complement activation, accounting for a 50-fold difference in virulence between mutant and wild-type viruses. We conclude that the C3 binding domain on gC is a major contributor to immune evasion and that this site explains at a molecular level why wild-type virus resists complement attack.