Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation
Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation
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DOI：
10.1128/jvi.00121-16
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发表时间：
2016-07-01
影响因子：
5.4
通讯作者：
Lilleri, Daniele
中科院分区：
文献类型：
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作者：
Gerna, Giuseppe;Percivalle, Elena;Lilleri, Daniele
人巨细胞病毒（HCMV）可能导致先天性感染的新生儿和免疫抑制移植受者的播散性/终末器官疾病。在病毒融合蛋白gB存在下，HCMV分别进入成纤维细胞和内皮/上皮细胞需要两种糖蛋白复合物，gH/gL/gO和gH/gL/pUL 128/pUL 130/pUL 131（gH/gL/pUL 128 L;称为五聚体）。此外，最近报道gH/gL/gO也是内皮/上皮细胞感染所需的。病毒进入人成纤维细胞涉及病毒包膜与质膜的融合，而进入内皮/上皮细胞涉及巨胞饮或内吞作用以及与内体的低pH依赖性融合。开发了针对gH、gB和五聚体的多个组分的大量中和单克隆抗体（MAb）。此外，最近分离出新型抗gO人单克隆抗体。已知上皮细胞以高感染复数感染野生HCMV株产生大量合胞体。在抗体浓度为10 μ g/ml时，将严重HCMV VR 1814感染的ARPE-19上皮细胞与针对五聚体的pUL 128 L部分的一种、两种或三种组分的中和性MAbs一起孵育，阻断了合胞体的形成，而针对相同浓度的gO、gH或gB的MAbs仅显示出部分抑制作用。原发性HCMV感染的恢复期血清也表现出阻断作用。这些发现表明，五聚体是上皮细胞中合胞体形成所必需的。
Human cytomegalovirus (HCMV) may cause disseminated/end-organ disease in congenitally infected newborns and immuno-suppressed transplant recipients. Two glycoprotein complexes, gH/gL/gO and gH/gL/pUL128/pUL130/pUL131 (gH/gL/pUL128L; referred to as the pentamer), are required for HCMV entry into fibroblasts and endothelial/epithelial cells, respectively, in the presence of the viral fusion protein gB. In addition, gH/gL/gO was recently reported to also be required for infection of endothelial/epithelial cells. Virus entry into human fibroblasts involves fusion of the virus envelope with the plasma membrane, whereas entry into endothelial/epithelial cells involves macropinocytosis or endocytosis and low-pH-dependent fusion with endosomes. A large set of neutralizing monoclonal antibodies (MAbs), directed to gH, gB, and multiple components of the pentamer, was developed. In addition, novel anti-gO human monoclonal antibodies were recently isolated. It is known that epithelial cell infection with a wild HCMV strain at a high multiplicity of infection produces a large number of syncytia. Incubation of heavily HCMV VR1814-infected ARPE-19 epithelial cells with neutralizing MAbs to one, two, or three components of the pUL128L portion of the pentamer blocked syncytium formation at an antibody concentration of 10 mu g/ml, whereas only a partial inhibitory effect was displayed for MAbs to gO, gH, or gB at the same concentration. A blocking effect was also exhibited by convalescent-phase sera from primary HCMV infections. These findings indicate that the pentamer is required for syncytium formation in epithelial cells.