Analysis of relationships between polymorphisms in the genes encoding the pentameric complex and neutralization of clinical cytomegalovirus isolates
Analysis of relationships between polymorphisms in the genes encoding the pentameric complex and neutralization of clinical cytomegalovirus isolates
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编码五聚体复合物的基因多态性与临床巨细胞病毒分离株中和之间的关系分析
DOI：
10.1016/j.vaccine.2018.08.054
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发表时间：
2018
期刊：
影响因子：
5.5
通讯作者：
Inoue Naoki
中科院分区：
文献类型：
--
作者：
Kobayashi Ryo;Abe Mao;Oguri Kohdai;Torikai Masaharu;Nishimura Tomohiro;Mori Hiroaki;Koshizuka Tetsuo;Inoue Naoki
简介由于先天性巨细胞病毒（CMV）感染是出生缺陷和发育异常的主要原因之一，因此开发针对 CMV 的疫苗和治疗性抗体至关重要。临床试验表明，基于糖蛋白B的亚单位疫苗（曾被认为是中和的主要目标）并没有诱导足够的保护性免疫。另一方面，据报道，用五聚体（gH/gL/UL128/UL130/UL131A的五聚体复合物）对动物进行免疫接种，可诱导强中和抗体。在这里，我们试图澄清临床分离株五聚体中存在的任何多态性改变是否影响抗五聚体抗体的中和。方法测定了25个日本临床分离株的编码五聚体成分的基因序列。使用基于 ARPE-19 的 CMV 报告细胞系测量两种血清阳性血清和抗五聚体血清对感染的中和作用。结果 UL128、UL130 和 UL131A ORF 的氨基酸序列多态性有限，并分为两大类。除 UL128 I140T 外，已识别的改变被映射到中和抗体识别的报告区域之外。抗五聚体血清对所有分离株的感染具有相似程度的中和作用，并且与多态性群体没有相关性。结论我们的研究结果表明，从 Merlin Fix 菌株制备的五聚体抗原诱导出的抗体能够将所有分离株的感染中和到相似的水平，并且抗五聚体抗体比人血清更好地中和 CMV 感染，这表明基于五聚体作为抗原的疫苗和治疗性抗体具有一定的前景。
IntroductionAs congenital cytomegalovirus (CMV) infection is one of the major causes of birth defects and developmental abnormalities, it is essential to develop vaccines and therapeutic antibodies against CMV. Clinical trials demonstrated that the subunit vaccine based on glycoprotein B, which had been believed to be the major target for neutralization, did not induce sufficient protective immunity. On the other hand, it has been reported that the immunization of animals with the Pentamer, the pentameric complex of gH/gL/UL128/UL130/UL131A, induced strong neutralizing antibodies. Here, we sought to clarify whether any polymorphic alterations present in the Pentamer of clinical isolates affect neutralization by anti-Pentamer antibodies.MethodsSequences of the genes encoding the Pentamer components of 25 Japanese clinical isolates were determined. Neutralization of infection by two seropositive sera and by anti-Pentamer serum was measured using a CMV reporter cell line based on ARPE-19.ResultsPolymorphisms of the amino acid sequence of UL128, UL130, and UL131A ORFs were limited and clustered into two major groups. The identified alterations, except UL128 I140T, were mapped outside of the reported regions recognized by neutralizing antibodies. Anti-Pentamer serum neutralized infection with all isolates to a similar degree and had no correlation with the polymorphic groups.ConclusionsOur findings indicate that Pentamer antigens prepared from Merlin Fix strain induce antibodies that neutralize infection with all isolates to a similar level and that anti-Pentamer antibodies neutralize CMV infection better than do human sera, suggesting that vaccines and therapeutic antibodies based on Pentamer as an antigen have some promise.