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Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus.
Gastroenterology. 2014 Jun; 146(7):1775-83.G

Abstract

BACKGROUND & AIMS

Many recipients of organ transplants develop chronic hepatitis, due to infection with the hepatitis E virus (HEV). Although chronic HEV infection is generally associated with immunosuppressive therapies, little is known about how different immunosuppressants affect HEV infection.

METHODS

A subgenomic HEV replication model, in which expression of a luciferase reporter gene is measured, and a full-length infection model were used. We studied the effects of different immunosuppressants, including steroids, calcineurin inhibitors (tacrolimus [FK506] and cyclosporin A), and mycophenolic acid (MPA, an inhibitor of inosine monophosphate dehydrogenase) on HEV replication in human hepatoma cell line Huh7. Expression of cyclophilins A and B (the targets of cyclosporin A) were knocked down using small hairpin RNAs.

RESULTS

Steroids had no significant effect on HEV replication. Cyclosporin A promoted replication of HEV in the subgenomic and infectious models. Knockdown of cyclophilin A and B increased levels of HEV genomic RNA by 4.0- ± 0.6-fold and 7.2- ± 1.9-fold, respectively (n = 6; P < .05). A high dose of FK506 promoted infection of liver cells with HEV. In contrast, MPA inhibited HEV replication. Incubation of cells with guanosine blocked the antiviral activity of MPA, indicating that the antiviral effects of this drug involve nucleotide depletion. The combination of MPA and ribavirin had a greater ability to inhibit HEV replication than MPA or ribavirin alone.

CONCLUSIONS

Cyclophilins A and B inhibit replication of HEV; this might explain the ability of cyclosporin A to promote HEV infection. On the other hand, the immunosuppressant MPA inhibits HEV replication. These findings should be considered when physicians select immunosuppressive therapies for recipients of organ transplants who are infected with HEV.

Authors+Show Affiliations

Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands.Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands.Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands; Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.Department of Surgery, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands.Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands; Division of Gastroenterology, University Health Network, Toronto, Canada.Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands.Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands.Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands. Electronic address: q.pan@erasmusmc.nl.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24582714

Citation

Wang, Yijin, et al. "Calcineurin Inhibitors Stimulate and Mycophenolic Acid Inhibits Replication of Hepatitis E Virus." Gastroenterology, vol. 146, no. 7, 2014, pp. 1775-83.
Wang Y, Zhou X, Debing Y, et al. Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. Gastroenterology. 2014;146(7):1775-83.
Wang, Y., Zhou, X., Debing, Y., Chen, K., Van Der Laan, L. J., Neyts, J., Janssen, H. L., Metselaar, H. J., Peppelenbosch, M. P., & Pan, Q. (2014). Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. Gastroenterology, 146(7), 1775-83. https://doi.org/10.1053/j.gastro.2014.02.036
Wang Y, et al. Calcineurin Inhibitors Stimulate and Mycophenolic Acid Inhibits Replication of Hepatitis E Virus. Gastroenterology. 2014;146(7):1775-83. PubMed PMID: 24582714.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. AU - Wang,Yijin, AU - Zhou,Xinying, AU - Debing,Yannick, AU - Chen,Kan, AU - Van Der Laan,Luc J W, AU - Neyts,Johan, AU - Janssen,Harry L A, AU - Metselaar,Herold J, AU - Peppelenbosch,Maikel P, AU - Pan,Qiuwei, Y1 - 2014/02/26/ PY - 2013/07/25/received PY - 2013/11/27/revised PY - 2014/02/19/accepted PY - 2014/3/4/entrez PY - 2014/3/4/pubmed PY - 2014/7/22/medline KW - Cell Culture Model KW - Immunity KW - Liver Disease KW - Transplantation SP - 1775 EP - 83 JF - Gastroenterology JO - Gastroenterology VL - 146 IS - 7 N2 - BACKGROUND & AIMS: Many recipients of organ transplants develop chronic hepatitis, due to infection with the hepatitis E virus (HEV). Although chronic HEV infection is generally associated with immunosuppressive therapies, little is known about how different immunosuppressants affect HEV infection. METHODS: A subgenomic HEV replication model, in which expression of a luciferase reporter gene is measured, and a full-length infection model were used. We studied the effects of different immunosuppressants, including steroids, calcineurin inhibitors (tacrolimus [FK506] and cyclosporin A), and mycophenolic acid (MPA, an inhibitor of inosine monophosphate dehydrogenase) on HEV replication in human hepatoma cell line Huh7. Expression of cyclophilins A and B (the targets of cyclosporin A) were knocked down using small hairpin RNAs. RESULTS: Steroids had no significant effect on HEV replication. Cyclosporin A promoted replication of HEV in the subgenomic and infectious models. Knockdown of cyclophilin A and B increased levels of HEV genomic RNA by 4.0- ± 0.6-fold and 7.2- ± 1.9-fold, respectively (n = 6; P < .05). A high dose of FK506 promoted infection of liver cells with HEV. In contrast, MPA inhibited HEV replication. Incubation of cells with guanosine blocked the antiviral activity of MPA, indicating that the antiviral effects of this drug involve nucleotide depletion. The combination of MPA and ribavirin had a greater ability to inhibit HEV replication than MPA or ribavirin alone. CONCLUSIONS: Cyclophilins A and B inhibit replication of HEV; this might explain the ability of cyclosporin A to promote HEV infection. On the other hand, the immunosuppressant MPA inhibits HEV replication. These findings should be considered when physicians select immunosuppressive therapies for recipients of organ transplants who are infected with HEV. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/24582714/Calcineurin_inhibitors_stimulate_and_mycophenolic_acid_inhibits_replication_of_hepatitis_E_virus_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(14)00278-9 DB - PRIME DP - Unbound Medicine ER -