Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong; Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong.
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
J Hepatol. 2021 Jun;74(6):1315-1324. doi: 10.1016/j.jhep.2020.12.028. Epub 2021 Apr 9.
BACKGROUND & AIMS: Rat hepatitis E virus (Orthohepevirus species C; HEV-C1) is an emerging cause of viral hepatitis in humans. HEV-C1 is divergent from other HEV variants infecting humans that belong to Orthohepevirus species A (HEV-A). This study assessed HEV-C1 antigenic divergence from HEV-A and investigated the impact of this divergence on infection susceptibility, serological test sensitivity, and vaccine efficacy.
Immunodominant E2s peptide sequences of HEV-A and HEV-C1 were aligned. Interactions of HEV-C1 E2s and anti-HEV-A monoclonal antibodies (mAbs) were modeled. Recombinant peptides incorporating E2s of HEV-A (HEV-A4 p239) and HEV-C1 (HEV-C1 p241) were expressed. HEV-A and HEV-C1 patient sera were tested using antibody enzymatic immunoassays (EIA), antigen EIAs, and HEV-A4 p239/HEV-C1 p241 immunoblots. Rats immunized with HEV-A1 p239 vaccine (Hecolin), HEV-A4 p239 or HEV-C1 p241 peptides were challenged with a HEV-C1 strain.
E2s sequence identity between HEV-A and HEV-C1 was only 48%. There was low conservation at E2s residues (23/53; 43.4%) involved in mAb binding. Anti-HEV-A mAbs bound HEV-C1 poorly in homology modeling and antigen EIAs. Divergence resulted in low sensitivity of commercial antigen (0%) and antibody EIAs (10-70%) for HEV-C1 diagnosis. Species-specific HEV-A4 p239/HEV-C1 p241 immunoblots accurately differentiated HEV-A and HEV-C1 serological profiles in immunized rats (18/18; 100%) and infected-patient sera (32/36; 88.9%). Immunization with Hecolin and HEV-A4 p239 was partially protective while HEV-C1 p241 was fully protective against HEV-C1 infection in rats.
Antigenic divergence significantly decreases sensitivity of hepatitis E serodiagnostic assays for HEV-C1 infection. Species-specific immunoblots are useful for diagnosing HEV-C1 and for differentiating the serological profiles of HEV-A and HEV-C1. Prior HEV-A exposure is not protective against HEV-C1. HEV-C1 p241 is an immunogenic vaccine candidate against HEV-C1.
Rat hepatitis E virus (HEV-C1) is a new cause of hepatitis in humans. Using a combination of methods, we showed that HEV-C1 is highly divergent from the usual cause of human hepatitis (HEV-A). This divergence reduces the capacity of existing tests to diagnose HEV-C1 and also indicates that prior exposure to HEV-A (via infection or vaccination) is not protective against HEV-C1.
大鼠戊型肝炎病毒（Orthohepevirus 种 C；HEV-C1）是人类新兴的病毒性肝炎病因。HEV-C1 与感染人类的其他 HEV 变体（属于 Orthohepevirus 种 A 的 HEV-A）存在差异。本研究评估了 HEV-C1 与 HEV-A 的抗原差异，并研究了这种差异对感染易感性、血清学检测敏感性和疫苗效力的影响。
对 HEV-A 和 HEV-C1 的免疫显性 E2s 肽序列进行了比对。模拟了 HEV-C1 E2s 与抗-HEV-A 单克隆抗体（mAb）的相互作用。表达了包含 HEV-A（HEV-A4 p239）和 HEV-C1（HEV-C1 p241）E2s 的重组肽。使用抗体酶免疫测定法（EIA）、抗原 EIA 和 HEV-A4 p239/HEV-C1 p241 免疫印迹法检测 HEV-A 和 HEV-C1 患者血清。用 HEV-A1 p239 疫苗（Hecolin）、HEV-A4 p239 或 HEV-C1 p241 肽免疫的大鼠用 HEV-C1 株进行攻毒。
HEV-A 和 HEV-C1 的 E2s 序列同一性仅为 48%。在与 mAb 结合相关的 E2s 残基（23/53；43.4%）中，保守性较低。抗-HEV-A mAb 在同源建模和抗原 EIA 中与 HEV-C1 结合不良。这种差异导致用于诊断 HEV-C1 的商业抗原（0%）和抗体 EIA（10-70%）的敏感性较低。种特异性 HEV-A4 p239/HEV-C1 p241 免疫印迹法准确地区分了免疫大鼠（18/18；100%）和感染患者血清（32/36；88.9%）的 HEV-A 和 HEV-C1 血清学特征。用 Hecolin 和 HEV-A4 p239 免疫可部分保护大鼠免受 HEV-C1 感染，而 HEV-C1 p241 则可完全保护大鼠免受 HEV-C1 感染。
抗原差异显著降低了用于诊断 HEV-C1 感染的戊型肝炎血清学检测的敏感性。种特异性免疫印迹法可用于诊断 HEV-C1，并区分 HEV-A 和 HEV-C1 的血清学特征。先前感染 HEV-A 并不能预防 HEV-C1。HEV-C1 p241 是一种针对 HEV-C1 的免疫原性疫苗候选物。
大鼠戊型肝炎病毒（HEV-C1）是人类肝炎的新病因。我们使用多种方法表明，HEV-C1 与人感染戊型肝炎的常见病因（HEV-A）存在高度差异。这种差异降低了现有检测方法诊断 HEV-C1 的能力，也表明先前接触 HEV-A（通过感染或接种疫苗）不能预防 HEV-C1。
