Mutations in the envelope protein associated with hepatitis B virus reactivation
Mutations in the envelope protein associated with hepatitis B virus reactivation
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与B型肝炎病毒再激活相关的包膜蛋白突变
DOI：
10.1111/hepr.13619
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发表时间：
2021-01
影响因子：
4.2
通讯作者：
Kiyoaki Ito
中科院分区：
文献类型：
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作者：
Kiyoaki Ito
癌症化疗或免疫抑制治疗后的乙肝病毒再激活(HBVr)可通过病毒学因素和宿主因素发生。在最新一期的《肝病研究》中，Tsuruya等人。东海大学医学部的报告称，在伊布鲁替尼治疗后的一例HBVr病例中存在病毒学因素。由于包膜蛋白中存在三重乙肝表面抗原逃逸突变体Q101K、M133L和G145A，患者在整个临床过程中仍为阴性。通常情况下，当HBVr出现在HBVr时，HBs Ag变为阳性。然而，三重HBs Ag逃逸突变被认为创造了一种隐蔽的乙肝感染表型，定义为用现有的检测方法检测出HBs Ag阴性的个体的肝脏中存在具有复制能力的HBVDNA和/或血液中存在HBVDNA。乙肝病毒包膜区域的突变(如免疫逃逸突变、PreS/S启动子突变或PreS/S剪接变异体)会导致隐匿性乙肝病毒感染。包膜蛋白α决定簇或主要亲水性环上第145位氨基酸的替换，特别是G145R突变，被称为免疫逃逸或疫苗逃逸突变。Q101K和M133L突变也被报道为逃逸突变。针对野生型病毒的中和抗体对这些突变的识别能力很差。此外，病毒颗粒分泌受损和免疫逃逸突变体的稳定性降低可能会限制突变体的全球传播。为什么在这种情况下，即使检测到逃逸突变，HBVDNA水平仍然如此高？我们先前的研究表明，包膜蛋白α决定簇中额外的N-连接糖基化位点(例如，M133T突变)可以挽救被免疫逃逸突变体破坏的病毒粒子分泌。最近，在HBVr患者、HBs和抗-HBs双阳性患者以及肝细胞癌患者中，额外的N-连锁糖基化突变的临床重要性被报道。以前的一篇综述文章描述了N-糖基化和N-糖链加工在乙肝病毒生物学和发病机制中的重要性。在目前的病例中，通过直接测序没有检测到额外的N-连接糖基化突变。最近的研究仅通过使用超深下一代测序检测到额外的糖基化突变。因此，在这种情况下，超深测序可能已经检测到了这些类型的突变。由于世界各地广泛接种乙肝疫苗，逃逸突变的流行程度正在增加，应考虑在包膜蛋白的主要亲水环中产生额外糖基化位点的突变。根据Tsuruya等人的报告，除了三重逃逸突变外，还检测到14个包膜蛋白突变。包膜蛋白的许多突变可能反映了宿主免疫系统暴露时间较长。我们先前通过下一代测序比较了HBVr患者和急性乙肝(AHB)患者的病毒学因素，发现HBVr患者的乙肝病毒全基因组突变位点频率明显高于AHB患者。与从核心启动子到前核的区域相比，包膜区域的这种趋势更加明显。在日本，虽然成年后通过水平传播感染AHB可导致HBVr，但据推测，大多数HBVr患者在儿童时期通过垂直传播或水平感染感染。另一方面，大多数成年AHB患者受到经济支持的感染：这项工作得到了AMD的支持，资助号为JP19fk0310118，资助金为科学研究C(资助号JP19K08479)。披露：K.I.从AbbVie和Gilead Sciences获得了研究资金。2020年12月8日收到；2020年12月31日修订；2021年1月10日接受。见《肝病研究》52：239-244的文章。在伊布鲁替尼治疗后乙肝病毒重新激活的病例，其中患者在整个临床过程中乙肝表面抗原仍为阴性。哥田拓也、安载和也、柴山顺介、伊藤忠志、吉高·阿拉斯、广罗斯顺治、田中康久、铃木秀树和香川隆弘；51：151-153DOI：10.1111/he.13619
Hepatitis B virus reactivation (HBVr) following cancer chemotherapy or immunosuppressive therapies can occur via both virological and host factors. In the current issue of Hepatology Research, Tsuruya et al. from the TokaiUniversity School of Medicine reported virological factors in an HBVr case following ibrutinib therapy. The patient remained negative for hepatitis B surface antigen (HBsAg) throughout the clinical course because of the presence of the triple HBsAg escape mutants Q101K, M133L and G145A in the envelope protein. Typically,HBsAg becomes positivewhen HBVr occurs in patients with resolvedHBV infection.However, triple HBsAg escape mutants are considered to create an occult HBV infection phenotype, defined as the presence of replication-competent HBV DNA in the liver and/ or HBV DNA in the blood of individuals who test negative for HBsAg using currently available assays. HBV mutations in the envelope region (e.g., immune escapemutants, preS/S promoter mutants, or preS/S splice variants) cause occult HBV infection. Amino acid substitutions at position 145, particularly the G145R mutation, in the α determinant or major hydrophilic loop of the envelope protein are known as immune escape or vaccine escape mutants.Q101KandM133Lmutations have also been reported as escape mutants. Neutralizing antibodies directed against the wild-type virus show poor recognition of these mutations. Additionally, the impaired virion secretion and the diminished stability of immune escape mutants may limit the global spread of the mutant. Why was the HBV DNA level so high in this case even though escape mutants were detected? Our previous study showed that additional N-linked glycosylation sites (e.g., M133T mutation) in the α determinant of the envelope protein rescued the virion secretion impaired by the immune escape mutants. Recently, the clinical importance of additional N-linked glycosylation mutations were reported in patients with HBVr, those who were HBsAg and anti-HBs double-positive, and patients with hepatocellular carcinoma. A previous review article described the importance of N-glycosylation and N-glycan processing in HBV biology and pathogenesis. In the current case, additional N-linked glycosylation mutations were not detected by direct sequencing. Recent studies detected additional glycosylation mutations by using only ultradeep next-generation sequencing. Therefore, ultradeep sequencing may have detected these types of mutations in this case. As the prevalence of escapemutants is increasing because of widespread HBV vaccination worldwide,mutations that create additional glycosylation sites in the major hydrophilic loop of the envelope protein should be considered. As reported by Tsuruya et al., 14 mutations in the envelope protein other than triple escape mutants were detected. Many mutations in the envelope protein may reflect a longer exposure time by the host immune system. We previously compared the virological factors between patients with HBVr and acute hepatitis B (AHB) by next-generation sequencing and found that the frequency of mutation sites in the whole genome of HBV derived from patients with HBVr was significantly higher than that in patients with AHB. This tendency was more apparent in the envelope region compared with the region from the core promoter to the precore. In Japan, although resolved after AHB infection via horizontal transmission during adulthood could cause HBVr, it is assumed that most patients with HBVr are infected via vertical transmission or horizontal infection in childhood. On the other hand, most adult patients with AHB are infected by Financial support: This workwas supported byAMEDunder grant number JP19fk0310118, Grant-in Aid for Scientific Research C (grant number JP19K08479). Disclosure: K.I. received research funding from AbbVie and Gilead Sciences. Received 8 December 2020; revision 31 December 2020; accepted 10 January 2021. See article in Hepatology Research 52: 239-244. Case of hepatitis B virus reactivation after ibrutinib therapy in which the patient remained negative for hepatitis B surface antigens throughout the clinical course Kota Tsuruya, Kazuya Anzai, Shunsuke Shioyama, Ayano Ito, Yoshitaka Arase, Shunji Hirose, Yasuhito Tanaka, Hidekazu Suzuki and Tatehiro Kagawa Hepatology Research 2021; 51: 151–153 doi: 10.1111/hepr.13619