Human Cytomegalovirus Escapes a Naturally Occurring Neutralizing Antibody by Incorporating It into Assembling Virions
Human Cytomegalovirus Escapes a Naturally Occurring Neutralizing Antibody by Incorporating It into Assembling Virions
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DOI：
10.1016/j.chom.2011.07.010
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发表时间：
2011-09-15
影响因子：
30.3
通讯作者：
Feire, Adam L.
中科院分区：
文献类型：
--
作者：
Manley, Kate;Anderson, John;Feire, Adam L.
人巨细胞病毒（CMV）是免疫功能低下患者常见但难以治疗的感染。MSL-109是从CMV血清阳性个体分离的人单克隆IgG，其识别介导进入的病毒糖蛋白H（gH）表面抗原复合物。尽管MSL-109在体外阻断CMV感染，但它在人体试验中缺乏足够的功效，并且从治疗的患者中分离的CMV表明MSL-109抗性的演变。为了理解CMV如何逃脱MSL-109，我们表征了MSL-109抗性CMV株。我们的研究结果阐明了一种非遗传性的逃逸机制，其中抗体被感染细胞选择性地吸收，并以剂量依赖性的方式并入组装的病毒体中。然后，抗性病毒利用掺入的抗体的Fc结构域感染初始非免疫细胞。这种耐药机制可以解释MSL-109的临床失败，说明病毒抗体逃逸的一般机制，并为抗病毒疫苗和治疗开发提供信息。
Human cytomegalovirus (CMV) is a common but difficult to treat infection of immunocompromised patients. MSL-109 is a human monoclonal IgG isolated from a CMV seropositive individual that recognizes the viral glycoprotein H (gH) surface antigen complexes that mediate entry. Although MSL-109 blocks CMV infection in vitro, it lacked sufficient efficacy in human trials, and CMV isolated from treated patients suggested the evolution of MSL-109 resistance. To understand how CMV escapes MSL-109, we characterized a MSL-109-resistant CMV strain. Our results elucidate a nongenetic escape mechanism in which the antibody is selectively taken up by infected cells and incorporated into assembling virions in a dose-dependent manner. The resistant virus then utilizes the Fc domain of the incorporated antibody to infect naive nonimmune cells. This resistance mechanism may explain the clinical failure of MSL-109, illustrate a general mechanism of viral antibody escape, and inform antiviral vaccine and therapeutic development.