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J Hepatol. 2014 Apr;60(4):723-31. doi: 10.1016/j.jhep.2013.11.022. Epub 2013 Dec 1.

Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor.

Author information

1
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, D 69120 Heidelberg, Germany.
2
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, D 69120 Heidelberg, Germany; Department of Nuclear Medicine, University Hospital Heidelberg, D 69120 Heidelberg, Germany.
3
Department of Nuclear Medicine, University Hospital Heidelberg, D 69120 Heidelberg, Germany.
4
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, D 69120 Heidelberg, Germany. Electronic address: Stephan.Urban@med.uni-heidelberg.de.

Abstract

BACKGROUND & AIMS:

Chronic hepatitis B and hepatitis D are global health problems caused by the human hepatitis B and hepatitis D virus. The myristoylated preS1 domain of the large envelope protein mediates specific binding to hepatocytes by sodium taurocholate co-transporting polypeptide (NTCP). NTCP is a bile salt transporter known to be inhibited by cyclosporin A. This study aimed to characterize the effect of cyclosporin A on HBV/HDV infection.

METHODS:

HepaRG cells, primary human hepatocytes, and susceptible NTCP-expressing hepatoma cell lines were applied for infection experiments. The mode of action of cyclosporin A was studied by comparing the effect of different inhibitors, cyclophilin A/B/C-silenced cell lines as well as NTCP variants and mutants. Bile salt transporter and HBV receptor functions were investigated by taurocholate uptake and quantification of HBVpreS binding.

RESULTS:

Cyclosporin A inhibited hepatitis B and D virus infections during and--less pronounced--prior to virus inoculation. Binding of HBVpreS to NTCP was blocked by cyclosporin A concentrations at 8 μM. An NTCP variant deficient in HBVpreS binding but competent for bile salt transport showed resistance to cyclosporin A. Silencing of cyclophilins A/B/C did not abrogate transporter and receptor inhibition. In contrast, tacrolimus, a cyclophilin-independent calcineurin inhibitor, was inactive.

CONCLUSIONS:

HBV and HDV entry via sodium taurocholate co-transporting polypeptide is inhibited by cyclosporin A. The interaction between the drug and the viral receptor is direct and overlaps with a functional binding site of the preS1 domain, which mediates viral entry.

KEYWORDS:

Binding domain; Cyclosporin A; Hepatitis B; Hepatitis D; Immunosuppressive; Myrcludex B; Sodium taurocholate cotransporting polypeptide; Tacrolimus; Viral entry

PMID:
24295872
DOI:
10.1016/j.jhep.2013.11.022
[Indexed for MEDLINE]

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