GUT｜復(fù)旦大學(xué)陳捷亮/張敏/袁正宏/張繼明教授共同通信研究發(fā)現(xiàn)功能性抗-preS1抗體應(yīng)答與慢性乙型肝炎病毒控制密切相關(guān)

乙型肝炎病毒（HBV）大表面蛋白的preS1抗原在病毒感染入胞環(huán)節(jié)發(fā)揮關(guān)鍵作用，但關(guān)于HBV慢性感染中preS1抗原及抗-preS1抗體的表達(dá)情況及其功能意義，尚缺乏系統(tǒng)研究。

肽P9~P11的氨基酸序列為AFGANSNNPDWDFNPNKDTWPDA，其中AFGANSNNPDWDF片段位于preS1與NTCP隧道區(qū)結(jié)合的界面，NPNKDTWPDA片段位于preS1與NTCP表面結(jié)合的界面。

近日，復(fù)旦大學(xué)陳捷亮、張敏、袁正宏、張繼明團(tuán)隊(duì)以共同通訊作者身份，在Gut（IF=41.111）發(fā)表最新研究論著，系統(tǒng)揭示了：慢性乙型肝炎（CHB）患者血清 preS1 抗原水平與 HBV DNA、HBsAg 及 HBeAg 呈顯著正相關(guān)；而抗 - preS1 IgG 抗體水平與 HBV DNA 呈顯著負(fù)相關(guān)，且在部分功能性治愈患者中可持續(xù)檢出。進(jìn)一步功能實(shí)驗(yàn)顯示，preS1 抗原低表達(dá)、抗 - preS1 IgG 高滴度的患者血清，可有效阻斷 preS1 與肝細(xì)胞受體 NTCP 的結(jié)合，展現(xiàn)出強(qiáng)效 HBV/HDV 中和活性；抗 - preS1 抗體所識(shí)別的線性表位，主要富集于 preS1 與 NTCP 結(jié)合的關(guān)鍵功能界面。在核苷（酸）類似物（NUC）停藥隊(duì)列中，基線高水平抗 - preS1 抗體與停藥后持續(xù)病毒學(xué)抑制顯著相關(guān)，提示其可作為預(yù)測(cè) CHB 功能性治愈與停藥安全性的重要免疫學(xué)標(biāo)志物。

圖：核苷（酸）類似物停藥后慢性乙型肝炎患者基線血清抗前S1 IgG水平及其對(duì)病毒學(xué)復(fù)發(fā)的預(yù)測(cè)效能。

綜上，該研究系統(tǒng)闡明了慢性乙型肝炎感染狀態(tài)下 preS1 抗原與抗 - preS1 抗體的表達(dá)規(guī)律及其潛在臨床價(jià)值：功能性抗 - preS1 抗體應(yīng)答可介導(dǎo)機(jī)體實(shí)現(xiàn)病毒控制，有助于核苷（酸）類似物（NUC）停藥后維持持續(xù)性病毒學(xué)抑制。該研究進(jìn)一步豐富并深化了人們對(duì)慢性乙型肝炎抗病毒免疫應(yīng)答機(jī)制的理解，同時(shí)明確了抗 - preS1 抗體在患者病毒學(xué)風(fēng)險(xiǎn)分層、個(gè)體化 HBsAg 特異性免疫狀態(tài)評(píng)估方面的重要應(yīng)用前景。

https://gut.bmj.com/content/early/2026/06/22/gutjnl-2025-337810

Title：Functional anti-preS1 antibody responses associated with viral control in chronic hepatitis BAbstract

BackgroundThe preS1 region of the HBV large surface protein binds sodium taurocholate cotransporting polypeptide (NTCP) to mediate viral entry, but the serological and functional relevance of circulating preS1 antigen and anti-preS1 antibodies in chronic hepatitis B (CHB) is not well defined.

ObjectiveTo characterise serum preS1 antigen and anti-preS1 IgG across CHB and evaluate their virological and functional significance.

DesignELISAs for preS1 antigen and anti-preS1 IgG were developed and applied to 549 individuals with chronic HBV infection, 107 individuals with functional cureand 110 vaccinated healthy controls. Neutralising activity was assessed using HBV and hepatitis D virus (HDV) infection models, preS1-NTCP competitive assays and peptide microarrays. Baseline anti-preS1 IgG was evaluated in 51 patients discontinuing nucleos(t)ide analogue (NUC) therapy.

ResultsPreS1 antigen was highest in hepatitis B e antigen (HBeAg)-positive patients and correlated with HBV DNA, hepatitis B surface antigen and HBeAg. Anti-preS1 IgG was detectable across disease phases, inversely associated with HBV DNA, positively correlated with alanine aminotransferase/aspartate aminotransferase and remained detectable in some individuals with functional cure. Sera with low preS1 and high anti-preS1 IgG showed potent HBV/HDV neutralising activity by inhibiting viral entry and blocking preS1-NTCP binding. Dominant linear epitopes mapped to preS1 regions involved in NTCP binding. High baseline anti-preS1 IgG was associated with sustained virological suppression after NUC withdrawal.

ConclusionPreS1 antigenaemia and anti-preS1 IgG exhibit distinct serological patterns linked to HBV replication and endogenous viral control. High anti-preS1 IgG confers potential neutralising activity and associates with sustained off-therapy suppression, highlighting its functional relevance as an indicator of host viral control.

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