Wahid Avista, Meyer Nele, Wundes Christine, Hüffner Lucas, Janshoff Saskia, Frericks Nicola, Friesland Martina, Dinkelborg Katja, Aliabadi Elmira, Laue Fenja, Cornberg Markus, Maasoumy Benjamin, Bremer Birgit, Pischke Sven, Müller Tobias, Wiesch Julian Zur Schulze, Benckert Julia, Ulrich Rainer G, Hardtke Svenja, Dörge Petra, Vondran Florian, Lohse Ansgar, Manns Michael Peter, Todt Daniel, Wedemeyer Heiner, Pietschmann Thomas, Steinmann Eike, Gömer André, Behrendt Patrick
Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
Department of Molecular and Medical Virology, Ruhr University Bochum, Germany.
Liver Int. 2025 Jul;45(7):e70183. doi: 10.1111/liv.70183.
The hepatitis E virus (HEV; species Paslahepevirus balayani) is a common human pathogenic and zoonotic virus that can cause both acute fulminant and chronic hepatitis. Despite its reputation as a hepatotropic virus, HEV infection is also associated with a number of extrahepatic diseases, including kidney disorders. However, the extent to which HEV replicates in kidney cells remains unclear. The present study aims to investigate the capacity of HEV to propagate in kidney cells in vitro and to assess whether HEV displays mutational signatures that correlate with compartmentalisation in vivo.
We use HEV cell culture models to study the replication cycle and the effect of antivirals in human kidney cell lines and primary cells. In addition, we identified patients with chronic HEV infection (n = 9) from which we then sequenced the viral RNA of urine, stools and plasma to analyse the viral sequence composition, to assess intra-host diversity and compartmentalisation (n = 2).
A wide range of human kidney cell lines as well as primary cells supports viral entry, replication and propagation of HEV in vitro. Interestingly, the broad-spectrum antiviral ribavirin was less effective in inhibiting HEV replication in some kidney cells. Sequencing of HEV RNA-directed RNA polymerase coding region from plasma, stool and urine and subsequent phylogenetic analysis revealed diversification of HEV into tissue-specific viral subpopulations. In particular, the viruses derived from urine were found to be distinct from those derived from plasma and stool.
In conclusion, kidney cells support the propagation of HEV in vitro and exhibit reduced sensitivity to antiviral treatment. Furthermore, HEV patient-derived sequences demonstrated compartmentalisation into distinct clusters that correlated with sample source. Collectively, these data indicate the potential for extrahepatic replication of HEV, which may result in clinically significant disease or serve as a reservoir for patient relapse.
HepNet-SofE study (NCT03282474).
戊型肝炎病毒（HEV；物种巴莱亚尼帕斯拉肝炎病毒）是一种常见的人类致病和人畜共患病毒，可导致急性暴发性肝炎和慢性肝炎。尽管戊型肝炎病毒素有嗜肝病毒之名，但戊型肝炎病毒感染也与包括肾脏疾病在内的多种肝外疾病有关。然而，戊型肝炎病毒在肾细胞中的复制程度仍不清楚。本研究旨在调查戊型肝炎病毒在体外肾细胞中的增殖能力，并评估戊型肝炎病毒是否表现出与体内分隔相关的突变特征。
我们使用戊型肝炎病毒细胞培养模型来研究其复制周期以及抗病毒药物在人肾细胞系和原代细胞中的作用。此外，我们确定了慢性戊型肝炎病毒感染患者（n = 9），然后对其尿液、粪便和血浆中的病毒RNA进行测序，以分析病毒序列组成，评估宿主内多样性和分隔情况（n = 2）。
多种人肾细胞系以及原代细胞在体外支持戊型肝炎病毒的进入、复制和增殖。有趣的是，广谱抗病毒药物利巴韦林在某些肾细胞中抑制戊型肝炎病毒复制的效果较差。对血浆、粪便和尿液中戊型肝炎病毒RNA指导的RNA聚合酶编码区进行测序，并随后进行系统发育分析，结果显示戊型肝炎病毒分化为组织特异性病毒亚群。特别是，发现源自尿液的病毒与源自血浆和粪便的病毒不同。
总之，肾细胞在体外支持戊型肝炎病毒的增殖，并且对抗病毒治疗的敏感性降低。此外，源自戊型肝炎患者的序列显示出分隔成与样本来源相关的不同簇。总体而言，这些数据表明戊型肝炎病毒肝外复制的可能性，这可能导致具有临床意义的疾病或成为患者复发的病毒库。
HepNet-SofE研究（NCT03282474）。
