Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice

At least 170 million people are chronically infected with hepatitis C virus (HCV). Owing to the narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular determinants...

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Published inHepatology (Baltimore, Md.) Vol. 62; no. 1; pp. 57 - 67
Main Authors Scull, Margaret A., Shi, Chao, de Jong, Ype P., Gerold, Gisa, Ries, Moritz, von Schaewen, Markus, Donovan, Bridget M., Labitt, Rachael N., Horwitz, Joshua A., Gaska, Jenna M., Hrebikova, Gabriela, Xiao, Jing W., Flatley, Brenna, Fung, Canny, Chiriboga, Luis, Walker, Christopher M., Evans, David T., Rice, Charles M., Ploss, Alexander
Format Journal Article
LanguageEnglish
Published United States Wiley Subscription Services, Inc 01.07.2015
Subjects
Animals
Disease Models, Animal
Hepacivirus - physiology
Hepatitis
Hepatitis C
Hepatitis C virus
Hepatocytes - virology
Hepatology
HIV
Host-Pathogen Interactions
Human immunodeficiency virus
Humans
Immunity, Innate
Lentivirus
Macaca mulatta
Mice
Pan troglodytes
Pathogenesis
Virus Internalization
Virus Replication
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Summary:At least 170 million people are chronically infected with hepatitis C virus (HCV). Owing to the narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular determinants of interspecies transmission and establish a novel immunocompetent model system, we examined the ability of HCV to infect hepatocytes from a small nonhuman primate, the rhesus macaque (Macaca mulatta). We show that the rhesus orthologs of critical HCV entry factors support viral glycoprotein‐dependent virion uptake. Primary hepatocytes from rhesus macaques are also permissive for HCV‐RNA replication and particle production, which is enhanced when antiviral signaling is suppressed. We demonstrate that this may be owing to the diminished capacity of HCV to antagonize mitochondrial antiviral‐signaling protein–dependent innate cellular defenses. To test the ability of HCV to establish persistent replication in vivo, we engrafted primary rhesus macaque hepatocytes into immunocompromised xenorecipients. Inoculation of resulting simian liver chimeric mice with either HCV genotype 1a or 2a resulted in HCV serum viremia for up to 10 weeks. Conclusion: Together, these data indicate that rhesus macaques may be a viable model for HCV and implicate host immunity as a potential species‐specific barrier to HCV infection. We conclude that suppression of host immunity or further viral adaptation may allow robust HCV infection in rhesus macaques and creation of a new animal model for studies of HCV pathogenesis, lentivirus coinfection, and vaccine development. (Hepatology 2015;62:57‐67)
Bibliography:Gisa Gerold is currently affiliated with the Institute of Experimental Virology Twincore‐Center for Experimental and Clinical Infectious Disease Research Hannover, Germany; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625, Hannover, Germany.
This work was supported, in part, by the National Institute for Diabetes, Digestive and Kidney Diseases (5 R01 AI090055‐05; to A.P. and C.M.R.), the National Institutes for Allergy and Infectious Diseases (NIAID; 2 R01 AI079031‐05A1, 1 R01 AI107301‐01, and 1 R56 AI106005‐01 [to A.P.] and 5 R01 AI072613‐08 [to C.M.R.]), and the National Institutes of Health (NIH) through the NIH Roadmap for Medical Research (grant no.: 1 R01 DK085713‐01). Additional funding was provided by the Starr Foundation, the Greenberg Medical Research Institute, the Richard Salomon Family Foundation, the Ronald A. Shellow, M.D., Memorial Fund, the MGM Mirage Voice Foundation, Gregory F. Lloyd Memorial contributions, and anonymous donors. The IHC core laboratory at NYU Medical Center is funded, in part, by the NYU Cancer Institute. The NYU Cancer Center is supported, in part, by grant 5P30CA016087‐32 from the National Cancer Institute. M.A.S. was supported by a National Research Service Award (F32 AI091207) from the NIAID. Y.P.J. was a recipient of an American Gastroenterological Association Research Scholar Award. A.P. is a recipient of the Liver Scholar Award from the American Liver Foundation. G.G. was supported by the Human Frontier Science Program (LT‐000048‐2009) and the German Academy of Science Leopoldina (LPDS 2009‐9). M.v.S. is a recipient of a postdoctoral fellowship from the German Research Foundation. J.M.G. is supported by cofunding from the NIAID on iNRSA 5T32GM007388. The funding sources were not involved in the study design, collection, analysis, or interpretation of data or in the writing of the report.
Potential conflict of interest: C.M.R. has equity in Apath, LLC, which holds commercial licenses for the Huh‐7.5 cell line, HCV cell culture system, the use of OCLN to construct HCV animal models, and the fluorescent cell‐based reporter system to detect HCV infection.
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present address: Institute of Experimental Virology Twincore – Center for Experimental and Clinical Infectious Disease Research Hannover, Germany; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), 30625, Hannover, Germany
ISSN:0270-9139
1527-3350
1527-3350
DOI:10.1002/hep.27773