Article first published online: 16 SEP 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 6, pages 1901–1912, December 2011
How to Cite
Andrus, L., Marukian, S., Jones, C. T., Catanese, M. T., Sheahan, T. P., Schoggins, J. W., Barry, W. T., Dustin, L. B., Trehan, K., Ploss, A., Bhatia, S. N. and Rice, C. M. (2011), Expression of paramyxovirus V proteins promotes replication and spread of hepatitis C virus in cultures of primary human fetal liver cells. Hepatology, 54: 1901–1912. doi: 10.1002/hep.24557
Potential conflict of interest: Dr. Rice owns stock in Apath, LLC.
Funded in part by the National Institutes of Health through the NIH Roadmap for Medical Research, Grant 1 R01 DK085713-01 (to C.M.R., A.P., S.N.B.) and NIH RO1 AI60561 (to L.B.D., S.M.), by the Greenberg Institute for Medical Research, and the Starr Foundation. L.A. was supported in part by a grant from the Hepatitis Research Foundation. T.P.S. was supported by National Research Service Award F32 AI084448-01). M.T.C. is the recipient of a Rockefeller University Women and Science Fellowship.
- Issue published online: 30 NOV 2011
- Article first published online: 16 SEP 2011
- Accepted manuscript online: 11 JUL 2011 12:28PM EST
- Manuscript Accepted: 1 JUL 2011
- Manuscript Received: 13 MAY 2011
Here we demonstrate that primary cultures of human fetal liver cells (HFLC) reliably support infection with laboratory strains of hepatitis C virus (HCV), although levels of virus replication vary significantly between different donor cell preparations and frequently decline in a manner suggestive of active viral clearance. To investigate possible contributions of the interferon (IFN) system to control HCV infection in HFLC, we exploited the well-characterized ability of paramyxovirus (PMV) V proteins to counteract both IFN induction and antiviral signaling. The V proteins of measles virus (MV) and parainfluenza virus 5 (PIV5) were introduced into HFLC using lentiviral vectors encoding a fluorescent reporter for visualization of HCV-infected cells. V protein-transduced HFLC supported enhanced (10 to 100-fold) levels of HCV infection relative to untransduced or control vector-transduced HFLC. Infection was assessed by measurement of virus-driven luciferase, by assays for infectious HCV and viral RNA, and by direct visualization of HCV-infected hepatocytes. Live cell imaging between 48 and 119 hours postinfection demonstrated little or no spread of infection in the absence of PMV V protein expression. In contrast, V protein-transduced HFLC showed numerous HCV infection events. V protein expression efficiently antagonized the HCV-inhibitory effects of added IFNs in HFLC. In addition, induction of the type III IFN, IL29, following acute HCV infection was inhibited in V protein-transduced cultures. Conclusion: These studies suggest that the cellular IFN response plays a significant role in limiting the spread of HCV infection in primary hepatocyte cultures. Strategies aimed at dampening this response may be key to further development of robust HCV culture systems, enabling studies of virus pathogenicity and the mechanisms by which HCV spreads in its natural host cell population. (HEPATOLOGY 2011;)