Human liver chimeric mice as a new model of chronic hepatitis E virus infection and preclinical drug evaluation

详细信息    查看全文

• 作者：Lena Allweiss¹ ; ^&dagger ; ; Sofia Gass¹ ; ^&dagger ; ; Katja Giersch¹ ; Anne Groth¹ ; Janine Kah¹ ; Tassilo Volz¹ ; Gianna Rapp¹ ; Anja Schö ; bel² ; Ansgar W. Lohse¹ ; ³ ; Susanne Polywka⁴ ; Sven Pischke¹ ; Eva Herker² ; Maura Dandri¹ ; ³ ; Marc Lü ; tgehetmann¹ ; ⁴ ; ^{mluetgeh@uke.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HEV ; hepatitis E virus ; uPA ; urokinase-type plasminogen activator ; SCID ; severe combined immunodeficiency ; PCR ; polymerase chain reaction ; ORF ; open reading frame ; UTR ; untranslated region ; USB ; uPA/SCID/beige ; i.v. ; intravenous ; GT ; genotype ; ELISA ; enzyme-linked immunosorbent assay ; LLoD ; lower limit of detection ; IU ; international unit ; p.i. ; post infection
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：64
• 期：5
• 页码：1033-1040
• 全文大小：2337 K

文摘

Hepatitis E virus (HEV) is a major cause of acute hepatitis as well as chronic infection in immunocompromised individuals; however, in vivo infection models are limited. The aim of this study was to establish a small animal model to improve our understanding of HEV replication mechanisms and permit the development of effective therapeutics.

Methods

UPA/SCID/beige mice repopulated with primary human hepatocytes were used for infection experiments with HEV genotype (GT) 1 and 3. Virological parameters were determined at the serological and intrahepatic level by real time PCR, immunohistochemistry and RNA in situ hybridization.

Results

Establishment of HEV infection was achieved after intravenous injection of stool-derived virions and following co-housing with HEV-infected animals but not via inoculation of serum-derived HEV. GT 1 infection resulted in a rapid rise of viremia and high stable titres in serum, liver, bile and faeces of infected mice for more than 25 weeks. In contrast, viremia in GT 3 infected mice developed more slowly and displayed lower titres in all analysed tissues as compared to GT 1. HEV-infected human hepatocytes could be visualized using HEV ORF2 and ORF3 specific antibodies and HEV RNA in situ hybridization probes. Finally, six-week administration of ribavirin led to a strong reduction of viral replication in the serum and liver of GT 1 infected mice.

Conclusion

We established an efficient model of HEV infection to test the efficacy of antiviral agents and to exploit mechanisms of HEV replication and interaction with human hepatocytes in vivo.