16型人乳头瘤病毒（HPV16）中和表位及型内变异分析

Neutralizing epitopes and intragenotypic variants of human papillomavirus 16 （HPV16）

世界范围内,宫颈癌是妇女第二位高发肿瘤.高危型人乳头瘤病毒（human papilloma-virus,HPV）持续感染是引发宫颈癌的主要原因,在所有高危型HPV中,HPV16流行最广泛.HPV主要衣壳蛋白（major capsid protein,L1）可以自组装成病毒样颗粒（virus-like particles,VLPs）,其形态及抗原性与天然病毒类似,可以刺激机体产生高效价保护性中和抗体.中和表位是HPV VLPs疫苗的结构基础,疫苗的效力主要取决于中和表位的完整性.目前基于中和单抗的HPV16表位研究取得了极大进展.随着免疫压力的增加,HPV16的型内变异株越来越多.1204条HPV16 L1氨基酸序列构建的进化树可以分为4个进化分支.同时,将其与114K参考序列相比,共挑选出8个＂高频突变位点＂,6个＂特有突变位点＂和20个＂表位相关位点＂.HPV诱导的中和抗体绝大多数都是型特异性的,但同一型别内的HPV所诱导的中和抗体对型别内的所有L1变异株是否都能保护尚无定论.剖析HPV16型的抗原表位及型内变异情况对设计高效价、高覆盖率的预防性疫苗至关重要.

Cervical cancer is the second most common cancer in women worldwide. It is clear that persistent infection of high-risk human papillomaviruses （ HR-HPVs ） is the main cause for this disease. Among the several HPV types associated with carcinoma, HPV-15 is the most prevalent type and present in about 50% of tumor specimens. The major capsid protein （ L1 ） of HPV can self-assemble into virus-like particles （VLPs） with immunogenicity similar to infectious virions. Neutralizing epitopes are the structural basis of the current prophylactic HPV vaccines. The efficacy of HPV vaccines is critically dependent upon the integrity of type-specific neutralizing epitopes. Recently, considerable headway has been made in stud- ying the epitopes of HPV16 based on neutralizing antibodies. Notably, more and more HPV16 variants have appeared along with increasing immune pressure. To study the phenotypic variations in HPV16 L1 protein, 1 204 naturally occurring sequences were analyzed and a phylogenetic tree was then constructed including four clades. Moreover, after compared the aforementioned sequences with the l14K reference sequence, eight ＂hot mutation sites＂, six ＂specialized mutation sites＂ and 20 ＂epitope-related mutation sites＂ were found. Generally, sera raised against VLPs can neutralize the corresponding HPV types, but not other types. However, it is not known whether intragenotypie variants of human papillomavirus type 16 （HPV-16） can be neutralized by sera vaccinated with a single variant VLPs. It is, therefore, imperative to understand the neu-tralizing epitopes and intragenotypic variants of HPV-16 for the production of prophylactic vaccines with high potency and broad coverage.