Identification of Broad-Genotype HPV L2 Neutralization Site for Pan-HPV Vaccine Development by a Cross-Neutralizing Antibody.
Identification of Broad-Genotype HPV L2 Neutralization Site for Pan-HPV Vaccine Development by a Cross-Neutralizing Antibody.
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通过交叉中和抗体鉴定广泛基因型 HPV L2 中和位点，用于泛 HPV 疫苗开发
DOI：
10.1371/journal.pone.0123944
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Xia N
中科院分区：
文献类型：
--
作者：
Wang D;Li Z;Xiao J;Wang J;Zhang L;Liu Y;Fan F;Xin L;Wei M;Kong Z;Yu H;Gu Y;Zhang J;Li S;Xia N
人乳头瘤病毒 (HPV) 是一种无包膜双链 DNA 病毒，导致 5% 的人类癌症。 HPV 衣壳由主要和次要结构蛋白 L1 和 L2 组成。 L1 蛋白与五聚体壳粒的构建块形成二十面体外壳，并且一个 L2 分子从衣壳的中心孔向外延伸。因此，L2 隐藏在 L1 内，只有当衣壳与宿主细胞相互作用时才会暴露。 L2 的低抗原变异意味着该蛋白可以为泛 HPV 疫苗的开发提供靶点。为了实现这一目标，我们在这里描述了一种抗 L2 单克隆抗体 14H6，它在基于伪病毒粒子的细胞中和测定中广泛中和至少 11 种 HPV，涵盖 6、11、16、18、31、33、35、45、52、58 和 59 型。 mAb 14H6 可识别位于 L2 蛋白的氨基酸 21 至 30 上的最小线性表位。丙氨酸扫描诱变和序列比对鉴定出参与 14H6 与 L2 结合的几个保守残基（Cys22、Lys23、Thr27、Cys28 和 Pro29）。该表位被移植到多种支架蛋白上，包括 HPV16 L1 病毒样颗粒、HBV 149 核心抗原和 CRM197。所得嵌合构建体在大肠杆菌中表达并高效纯化。使用这些泛 HPV 候选疫苗进行免疫接种可在小鼠体内引发高滴度的 L2 特异性抗体，并赋予强大的（3-log）跨基因型中和滴度，包括针对 HPV11、16、18、45、52、58 和 59。这些发现将有助于开发基于 L2 的泛 HPV 疫苗。
Human Papillomavirus (HPV), a non-enveloped, double-stranded DNA virus, is responsible for 5% of human cancers. The HPV capsid consists of major and minor structural proteins, L1 and L2. L1 proteins form an icosahedral shell with building blocks of the pentameric capsomere, and one L2 molecule extends outward from the central hole of the capsid. Thus, L2 is concealed within L1 and only becomes exposed when the capsid interacts with host cells. The low antigenic variation of L2 means that this protein could offer a target for the development of a pan-HPV vaccine. Toward this goal, here we describe an anti-L2 monoclonal antibody, 14H6, which broadly neutralizes at least 11 types of HPV, covering types 6, 11, 16, 18, 31, 33, 35, 45, 52, 58 and 59, in pseudovirion—based cell neutralization assay. The mAb 14H6 recognizes a minimal linear epitope located on amino acids 21 to 30 of the L2 protein. Alanine scanning mutagenesis and sequence alignment identified several conserved residues (Cys22, Lys23, Thr27, Cys28 and Pro29) that are involved in the 14H6 binding with L2. The epitope was grafted to several scaffolding proteins, including HPV16 L1 virus-like particles, HBV 149 core antigen and CRM197. The resultant chimeric constructs were expressed in Escherichia coli and purified with high efficiency. Immunization with these pan-HPV vaccine candidates elicited high titers of the L2-specific antibody in mice and conferred robust (3-log) titers of cross-genotype neutralization, including against HPV11, 16, 18, 45, 52, 58 and 59. These findings will help in the development of an L2-based, pan-HPV vaccine.
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影响因子：
5.5
作者：
Kalnin, Kirin;Tibbitts, Timothy;Yan, Yanhua;Stegalkina, Svetlana;Shen, Lihua;Costa, Victor;Sabharwal, Robert;Anderson, Stephen F.;Day, Patricia M.;Christensen, Neil;Schiller, John T.;Jagu, Subhashini;Roden, Richard B. S.;Almond, Jeffrey;Kleanthous, Harold
通讯作者：
Kleanthous, Harold
影响因子：
6.4
作者：
Muñoz, N;Bosch, FX;Meijer, CJLM
通讯作者：
Meijer, CJLM
影响因子：
3.7
作者：
Kondo, Kazunari;Ishii, Yoshiyuki;Kanda, Tadahito
通讯作者：
Kanda, Tadahito
影响因子：
3.7
作者：
Cubie, Heather A.
通讯作者：
Cubie, Heather A.
影响因子：
4.8
作者：
Li, SW;Zhang, J;Xia, NS
通讯作者：
Xia, NS