Identification and Mapping of HBsAg Loss-Related B-Cell Linear Epitopes in Chronic HBV Patients by Peptide Array.
Identification and Mapping of HBsAg Loss-Related B-Cell Linear Epitopes in Chronic HBV Patients by Peptide Array.
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通过肽阵列在慢性HBV患者中与HBSAG损失相关的B细胞线性表位的鉴定和映射。
DOI：
10.3389/fimmu.2021.767000
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tang L
中科院分区：
文献类型：
--
作者：
Gu S;Liu Z;Lin L;Zhong S;Ma Y;Li X;Ye G;Wen C;Li Y;Tang L
针对乙型肝炎病毒（HBV）编码蛋白的免疫原性靶点的鉴定将为开发潜在的抗体疗法提供关键进展。B型肝炎病毒（HBV）编码蛋白的免疫原性靶点的鉴定将为开发潜在的抗体疗法提供关键进展。在这项研究中，招募了63例未经治疗的慢性HBV感染患者和46例抗病毒治疗后达到B肝炎表面抗原丢失（sAg丢失）的患者。此外，6例从B e抗原阳性慢性感染期（eAg+CInf）过渡到肝炎期（eAg+CHep）的患者从现实临床实践中入组。此外，对替比夫定治疗的eAg+CHep患者和来自停止治疗队列的复发者或应答者进行了纵向研究。流式细胞仪检测B细胞的频率和功能。我们设计了由HBV编码的表面（S）、核心（C）和聚合酶（P）蛋白的15聚体重叠肽组成的肽阵列，并用血清对B细胞线性表位进行了筛选。与sAg+患者相比，sAg-患者的幼稚B细胞和浆母细胞增加，而总记忆、激活记忆（AM）和非典型记忆（AtM）B细胞减少。重要的是，纵向观察发现AtM B细胞与成功的治疗停药相关。有趣的是，我们鉴定了六个S特异性显性表位（S33、S34、S45、S76、S78和S89）和一个C特异性显性表位（C37），其与来自sAg-患者的大多数血清反应。值得注意的是，在伴有丙氨酸氨基转移酶（ALT）发作的CHep患者中检测到的B细胞线性表位多于非发作CInf患者，ALT发作患者压倒性地识别了5个B细胞线性表位（S4、S5、S10、S11和S68）。CHep患者对C和P蛋白表位的识别率明显高于CInf患者。值得注意的是，当ALT非发作患者进入发作期时，观察到阳性表位数量统计学显著升高。此外，在基线时确定的S76被证实与替比夫定治疗48周后的完全缓解相关。综上所述，我们确定了几个慢性HBV感染的功能性治疗相关的B细胞线性表位，这些表位可能作为疫苗候选人，以引发中和抗体来治疗HBV感染。
Identification of immunogenic targets against hepatitis B virus (HBV)-encoded proteins will provide crucial advances in developing potential antibody therapies. In this study, 63 treatment-naïve patients with chronic HBV infection and 46 patients who achieved hepatitis B surface antigen loss (sAg loss) following antiviral treatment were recruited. Moreover, six patients who transitioned from the hepatitis B e antigen-positive chronic infection phase (eAg+CInf) to the hepatitis phase (eAg+CHep) were enrolled from real-life clinical practice. Additionally, telbivudine-treated eAg+CHep patients and relapsers or responders from an off-treatment cohort were longitudinally studied. The frequencies and function of B cells were assessed by flow cytometry. We devised a peptide array composed of 15-mer overlapping peptides of HBV-encoded surface (S), core (C), and polymerase (P) proteins and performed a screening on B-cell linear epitopes with sera. Naïve B cells and plasmablasts were increased, whereas total memory, activated memory (AM), and atypical memory (AtM) B cells were reduced in sAg- patients compared with sAg+ patients. Importantly, longitudinal observations found that AtM B cells were associated with successful treatment withdrawal. Interestingly, we identified six S-specific dominant epitopes (S33, S34, S45, S76, S78, and S89) and one C-specific dominant epitope (C37) that reacted with the majority of sera from sAg- patients. Of note, more B-cell linear epitopes were detected in CHep patients with alanine aminotransferase (ALT) flares than in nonflare CInf patients, and five B-cell linear epitopes (S4, S5, S10, S11, and S68) were overwhelmingly recognized by ALT flare patients. The recognition rates of epitopes on C and P proteins were significantly increased in CHep patients relative to CInf patients. Strikingly, a statistically significant elevation in the number of positive epitopes was observed when ALT nonflare patients shifted into the flare phase. Moreover, S76 identified at baseline was confirmed to be associated with a complete response after 48 weeks of telbivudine therapy. Taken together, we identified several functional cure-related B-cell linear epitopes of chronic HBV infection, and these epitopes may serve as vaccine candidates to elicit neutralizing antibodies to treat HBV infection.
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4.6
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