The Epstein-Barr Virus Glycoprotein gp150 Forms an Immune-Evasive Glycan Shield at the Surface of Infected Cells

Cell-mediated immunity plays a key role in host control of viral infection. This is exemplified by life-threatening reactivations of e.g. herpesviruses in individuals with impaired T-cell and/or iNKT cell responses. To allow lifelong persistence and virus production in the face of primed immunity, herpesviruses exploit immune evasion strategies. These include a reduction in viral antigen expression during latency and a number of escape mechanisms that target antigen presentation pathways. Given the plethora of foreign antigens expressed in virus-producing cells, herpesviruses are conceivably most vulnerable to elimination by cell-mediated immunity during the replicative phase of infection. Here, we show that a prototypic herpesvirus, Epstein-Barr virus (EBV), encodes a novel, broadly acting immunoevasin, gp150, that is expressed during the late phase of viral replication. In particular, EBV gp150 inhibits antigen presentation by HLA class I, HLA class II, and the non-classical, lipid-presenting CD1d molecules. The mechanism of gp150-mediated T-cell escape does not depend on degradation of the antigen-presenting molecules nor does it require gp150’s cytoplasmic tail. Through its abundant glycosylation, gp150 creates a shield that impedes surface presentation of antigen. This is an unprecedented immune evasion mechanism for herpesviruses. In view of its likely broader target range, gp150 could additionally have an impact beyond escape of T cell activation. Importantly, B cells infected with a gp150-null mutant EBV displayed rescued levels of surface antigen presentation by HLA class I, HLA class II, and CD1d, supporting an important role for iNKT cells next to classical T cells in fighting EBV infection. At the same time, our results indicate that EBV gp150 prolongs the timespan for producing viral offspring at the most vulnerable stage of the viral life cycle.

细胞介导免疫（cell-mediated immunity）在宿主管控病毒感染的过程中发挥核心作用。当个体的T细胞和/或不变自然杀伤T（iNKT）细胞功能受损时，疱疹病毒会出现致死性再激活，这便是该免疫机制重要性的典型体现。为在已致敏的宿主免疫环境中实现终身持续感染与病毒增殖，疱疹病毒进化出多种免疫逃逸策略，包括潜伏感染期病毒抗原表达的下调，以及一系列靶向抗原呈递通路的逃逸机制。鉴于病毒感染细胞会表达大量外来抗原，疱疹病毒在感染的复制阶段极易受到细胞介导免疫的清除。本研究显示，原型疱疹病毒EB病毒（Epstein-Barr virus，EBV）编码一种新型广谱免疫逃逸蛋白糖蛋白150（gp150），该蛋白在病毒复制的晚期阶段表达。具体而言，EBV gp150可抑制人类白细胞抗原I类（HLA class I）、人类白细胞抗原II类（HLA class II）以及非经典脂质呈递CD1d分子的抗原呈递功能。gp150介导的T细胞逃逸机制既不依赖抗原呈递分子的降解，也无需gp150的胞质尾区参与。通过高度糖基化修饰，gp150可形成一道物理屏障，阻碍抗原的细胞表面呈递，这是疱疹病毒前所未有的免疫逃逸机制。鉴于其可能具备更广泛的靶标范围，gp150的功能或许不止于介导T细胞逃逸。值得注意的是，感染gp150敲除突变型EB病毒的B细胞，其人类白细胞抗原I类、II类以及CD1d介导的抗原表面呈递水平得以恢复，这表明除经典T细胞外，iNKT细胞在对抗EB病毒感染中同样发挥关键作用。与此同时，我们的研究结果表明，在病毒生命周期最脆弱的复制阶段，EBV gp150可延长病毒子代的产生周期。