近日,，國際病毒學(xué)核心期刊Journal of Virology在線刊登了中科院武漢病毒研究所陳新文研究員帶領(lǐng)的研究團(tuán)隊(duì)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變異研究中取得新的重要進(jìn)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)包膜表面的重要結(jié)構(gòu)蛋白，能誘導(dǎo)機(jī)體產(chǎn)生保護(hù)性免疫應(yīng)答,。由HBsAg第124-147位氨基酸組成的“a”決定簇具有復(fù)雜的空間構(gòu)象,，含有多個(gè)重要的免疫表位。發(fā)生在“a”決定簇或其周圍的變異影響HBsAg與抗體的結(jié)合,，引起病毒的免疫逃逸,。
K122I取代和G145R取代是“a”決定簇上最為經(jīng)典的氨基酸取代。研究發(fā)現(xiàn),，G145R突變株可穩(wěn)定存在,，并可持續(xù)數(shù)年保持高滴度的復(fù)制水平,，此外還能在人群中及家族內(nèi)進(jìn)行水平傳播。雖然在122和145位點(diǎn)還發(fā)現(xiàn)了其他氨基酸形式的取代,，如K122N,、G145A、G145K等,，但是這些取代形式的出現(xiàn)頻率和影響程度遠(yuǎn)低于K122I取代和G145R取代,。不過，其中的機(jī)制并不明了,，對于病毒變異及進(jìn)化的意義尚不清楚,。
為此，陳新文研究員領(lǐng)導(dǎo)的研究小組采用免疫熒光染色及小鼠尾靜脈高壓水注射模型,，開展了一系列體內(nèi)外研究,，證明了除氨基酸所在的位置之外，其側(cè)鏈的理化特性也是影響病毒發(fā)生免疫逃逸的重要決定因素,，闡釋了K122I取代和G145R取代頻繁出現(xiàn)對病毒變異及進(jìn)化的意義,，更證實(shí)了有效的抗體應(yīng)答對于中和并清除病毒起著關(guān)鍵作用。
研究結(jié)果還發(fā)現(xiàn),，抗體應(yīng)答對不同基因型病毒的清除效率也有不同，因此針對某種基因型病毒的正常的抗體應(yīng)答可能并不能有效防御不同基因型病毒的感染,。該發(fā)現(xiàn)與近期發(fā)表在New England Journal of Medicine雜志上的臨床結(jié)果相互印證（Stramer SL,，et al. N. Engl. J. Med. 2011，364：236-247）,，為指導(dǎo)臨床HBV疫苗的使用提供了有力的理論依據(jù),。
該研究得到了國家基礎(chǔ)研究發(fā)展計(jì)劃的大力支持。（生物谷Bioon.com）
doi:10.1128/JVI.06353-11
PMC:
PMID:
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.
