近日，国际病毒学核心期刊Journal of Virology在线刊登了中科院武汉病毒研究所陈新文研究员带领的研究团队的最新研究成果“Amino acid substitutions at the positions 122 and 145 of hepatitis B surface antigen (HBsAg) determine the antigenicity and immunogenicity of HBsAg and influence in vivo HBsAg clearance ，”，文章中，研究者揭示了在乙型肝炎病毒表面抗原变异研究中取得新的重要进展。
乙型肝炎病毒表面抗原（Hepatitis B Surface Antigen， HBsAg）是位于乙型肝炎病毒（HBV)包膜表面的重要结构蛋白，能诱导机体产生保护性免疫应答。由HBsAg第124-147位氨基酸组成的“a”决定簇具有复杂的空间构象，含有多个重要的免疫表位。发生在“a”决定簇或其周围的变异影响HBsAg与抗体的结合，引起病毒的免疫逃逸。
K122I取代和G145R取代是“a”决定簇上最为经典的氨基酸取代。研究发现，G145R突变株可稳定存在，并可持续数年保持高滴度的复制水平，此外还能在人群中及家族内进行水平传播。虽然在122和145位点还发现了其他氨基酸形式的取代，如K122N、G145A、G145K等，但是这些取代形式的出现频率和影响程度远低于K122I取代和G145R取代。不过，其中的机制并不明了，对于病毒变异及进化的意义尚不清楚。
为此，陈新文研究员领导的研究小组采用免疫荧光染色及小鼠尾静脉高压水注射模型，开展了一系列体内外研究，证明了除氨基酸所在的位置之外，其侧链的理化特性也是影响病毒发生免疫逃逸的重要决定因素，阐释了K122I取代和G145R取代频繁出现对病毒变异及进化的意义，更证实了有效的抗体应答对于中和并清除病毒起着关键作用。
研究结果还发现，抗体应答对不同基因型病毒的清除效率也有不同，因此针对某种基因型病毒的正常的抗体应答可能并不能有效防御不同基因型病毒的感染。该发现与近期发表在New England Journal of Medicine杂志上的临床结果相互印证（Stramer SL，et al. N. Engl. J. Med. 2011，364：236-247），为指导临床HBV疫苗的使用提供了有力的理论依据。
该研究得到了国家基础研究发展计划的大力支持。（生物谷Bioon.com）
doi:10.1128/JVI.06353-11
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Amino acid substitutions at the positions 122 and 145 of hepatitis B surface antigen (HBsAg) determine the antigenicity and immunogenicity of HBsAg and influence in vivo HBsAg clearance
Chunchen Wu1,2, Wanyu Deng1,2, Liu Deng1, Liang Cao1, Bo Qin1, Songxia Li1, Yun Wang1, Rongjuan Pei1, Dongliang Yang3, Mengji Lu1,2,4,* and Xinwen Chen1,*
A variety of amino acid (8) substitutions such as K122I and G145R have been identified around or within the “a” determinant of hepatitis B surface antigen (HBsAg), impair HBsAg secretion and antibody binding and may be responsible for immune escape in patients. In this study, we examined how different substitutions at aa positions 122 and 145 of HBsAg influence HBsAg expression, secretion, and recognition by anti-HBs antibodies. The results showed that the hydrophobicity, the presence of the phenyl group, and the charges in the side chain of the aa residues at position 145 reduced HBsAg secretion and impaired reactivity with anti-HBs antibodies. Only the substitution K122I at the position 122 affected HBsAg secretion and recognition by anti-HBs antibodies. Genetic immunization in mice demonstrated that priming of anti-HBs antibody response was strongly impaired by the substitutions K122I, G145R, and others like G145I, G145W, and G145E. Mice preimmunized with wtHBsAg or variant HBsAg (vtHBsAg) were challenged by hydrodynamic injection (HI) with a replication competent hepatitis B virus (HBV) clone. HBsAg persisted in peripheral blood for at least 3 days after HI in mice preimmunized with vtHBsAg but undetectable in mice preimmunized with wtHBsAg indicating vtHBsAg may fail to induce proper immune responses for efficient HBsAg clearance. In conclusion, the biochemical properties of aa residues at positions 122 and 145 of HBsAg have a major impact on the antigenicity and immunogenecity. In addition, the presence of proper anti-HBs antibodies is indispensable for neutralization and clearance of HBsAg during HBV infection.
