Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins

doi:10.1073/pnas.0700760104

Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins

Departments of *Molecular Genetics,
^†Microbiology, and
^‡Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046

Communicated by Michael S. Brown, University of Texas Southwestern Medical Center, Dallas, TX, January 29, 2007 (received for review January 15, 2007)

Abstract

Hepatitis C virus (HCV) and triglyceride-rich very low-density lipoproteins (VLDLs) both are secreted uniquely by hepatocytes and circulate in blood in a complex. Here, we isolated from human hepatoma cells the membrane vesicles in which HCV replicates. These vesicles, which contain the HCV replication complex, are highly enriched in proteins required for VLDL assembly, including apolipoprotein B (apoB), apoE, and microsomal triglyceride transfer protein. In hepatoma cells that constitutively produce infectious HCV, HCV production is reduced by two agents that block VLDL assembly: an inhibitor of microsomal triglyceride transfer protein and siRNA directed against apoB. These results provide a possible explanation for the restriction of HCV production to the liver and suggest new cellular targets for treatment of HCV infection.

Footnotes

^§To whom correspondence should be addressed. E-mail: jin.ye{at}utsouthwestern.edu
Author contributions: H.H. and F.S. contributed equally to this work; F.S. and J.Y. designed research; H.H., F.S., D.M.O., and W.L. performed research; Y.C. and M.G. contributed new reagents/analytic tools; H.H., M.G., and J.Y. analyzed data; and J.Y. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0700760104/DC1.
Abbreviations:

HCV,

hepatitis C virus;

MTP,

microsomal triglyceride transfer protein;

VLDL,

very low-density lipoproteins;

apo,

apolipoprotein;

ER,

endoplasmic reticulum;

NS,

nonstructural;

endo H,

endoglycosidase H.
Freely available online through the PNAS open access option.