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Alisporivir inhibition of hepatocyte cyclophilins reduces HBV replication and hepatitis B surface antigen production

Significance statement

The major findings in the study were firstly, that cellular cyclophilins are involved in multiple steps of HBV life cycle; secondly, that a combination of cyclophilin inhibitors like Alisporivir plus direct antivirals (HBV DNA pol inhibitors) could be a useful combination to achieve HBsAg clearance, i.e. HBV cure. Alisporivir and other cyclophilin inhibitors could impact HBV life cycle at multiple sites in hepatocytes

1. Reduce production of new virions and re-circulation of HBV nucleocapsids from cytoplasm to nucleus

2. Blocking CYPD inhibits HBxAg regulation of HBV replication

3. Block CYPA and HBsAg interactions and CYPA involvement in HBV envelope formation and HBsAg secretion

4. Block NTCP – the functional receptor for HBV and HDV thus preventing entry into non-infected hepatocytes

Alisporivir inhibition of hepatocyte cyclophilins reduces HBV replication and hepatitis B surface antigen production.. Global Medical Discovery

 

 

 

 

 

 

 

Journal Reference

Phillips S1, Chokshi S1, Chatterji U2, Riva A1, Bobardt M2, Williams R1, Gallay P2, Naoumov NV3. Gastroenterology. 2015 ;148(2):403-14.e7.

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Abstract

BACKGROUND & AIMS:

Cyclophilins are host factors required for hepatitis C virus replication. Cyclophilin inhibitors such as alisporivir have shown strong anti-hepatitis C virus activity in vitro and in clinical studies. However, little is known about whether hepatocyte cyclophilins are involved in the hepatitis B virus (HBV) life cycle. We investigated the effects of 2 cyclophilin inhibitors (alisporivir and NIM811)  in HBV replication and hepatitis Bsurface antigen (HBsAg) production in cell lines.

METHODS:

Liver-derived cell lines producing full-length HBV and HBsAg particles, owing to stable (HepG2215) or transient (HuH-7) transfection, or infected with HBV (HepaRG cells; Invitrogen [Carlsbad, CA]), were incubated with alisporivir or NIM811 alone, or alisporivir in combination with a direct antiviral (telbivudine). The roles of individual cyclophilins in drug response was evaluated by small interfering RNA knockdown of cyclophilin (CYP)A, CYPC, or CYPD in HepG2215 cells, or CYPA knockdown in HuH-7 cells. The kinetics of antiviral activity were assessed based on levels ofHBV DNA and HBsAg and Southern blot analysis.

RESULTS:

In HepG2215, HuH-7, and HepaRG cells, alisporivir reduced intracellular and secreted HBV DNA, in a dose-dependent manner. Knockdown of CYPA, CYPC, or CYPD (reduced by 80%) significantly reduced levels of HBV DNA and secreted HBsAg. Knockdown of CYPA significantly reduced secretion of HBsAg, leading to accumulation of intracellular HBsAg; the addition of alisporivir  greatly reduced levels of HBsAg in these cells. The combination of alisporivir  and telbivudine had greater antiviral effects than those of telbivudine or alisporivir alone.

CONCLUSIONS:

Alisporivir inhibition of cyclophilins in hepatocyte cell lines  reduces  replication of HBV DNA and HBsAg production and secretion. These effects are potentiated in combination with direct antiviral agents that target HBV-DNA polymerase.

Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

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