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Thromboxane A2 synthase inhibitors prevent production of infectious hepatitis C virus in mice with humanized livers.

Abstract：

BACKGROUND & AIMS:A 3-dimensional (3D) culture system for immortalized human hepatocytes (HuS-E/2 cells) recently was shown to support the lifecycle of blood-borne hepatitis C virus (HCV). We used this system to identify proteins that are active during the HCV lifecycle under 3D culture conditions. METHODS:We compared gene expression profiles of HuS-E/2 cells cultured under 2-dimensional and 3D conditions. We identified signaling pathways that were activated differentially in the cells, and analyzed their functions in the HCV lifecycle using a recombinant HCV-producing cell-culture system, with small interfering RNAs and chemical reagents. We investigated the effects of anti-HCV reagents that altered these signaling pathways in mice with humanized livers (carrying human hepatocytes). RESULTS:Microarray analysis showed that cells cultured under 2-dimensional vs 3D conditions expressed different levels of messenger RNAs encoding prostaglandin synthases. Small interfering RNA-mediated knockdown of thromboxane A2 synthase (TXAS) and incubation of hepatocytes with a TXAS inhibitor showed that this enzyme is required for production of infectious HCV, but does not affect replication of the HCV genome or particle release. The TXAS inhibitor and a prostaglandin I2 receptor agonist, which has effects that are opposite those of thromboxane A2, reduced serum levels of HCV and inhibited the infection of human hepatocytes by blood-borne HCV in mice. CONCLUSIONS:An inhibitor of the prostaglandin synthase TXAS inhibits production of infectious HCV particles in cultured hepatocytes and HCV infection of hepatocytes in mice with humanized livers. It therefore might be therapeutic for HCV infection.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Abe Y,Aly HH,Hiraga N,Imamura M,Wakita T,Shimotohno K,Chayama K,Hijikata M

doi

10.1053/j.gastro.2013.05.014

subject

Has Abstract

pub_date

2013-09-01 00:00:00

pages

658-67.e11

issue

3

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(13)00746-4

journal_volume

145

pub_type

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