Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice.

TitleHepatitis C virus infects rhesus macaque hepatocytes and simianized mice.
Publication TypeJournal Article
Year of Publication2015
AuthorsScull, MA, Shi, C, de Jong, YP, Gerold, G, Ries, M, von Schaewen, M, Donovan, BM, Labitt, RN, Horwitz, JA, Gaska, JM, Hrebikova, G, Xiao, JW, Flatley, B, Fung, C, Chiriboga, L, Walker, CM, Evans, DT, Rice, CM, Ploss, A
JournalHepatology
Volume62
Issue1
Pagination57-67
Date Published2015 Jul
ISSN1527-3350
KeywordsAnimals, Disease Models, Animal, Hepacivirus, Hepatitis C, Hepatocytes, Host-Pathogen Interactions, Humans, Immunity, Innate, Macaca mulatta, Mice, Virus Internalization, Virus Replication
Abstract

<p><b>UNLABELLED: </b>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.</p><p><b>CONCLUSION: </b>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.</p>

DOI10.1002/hep.27773
Alternate JournalHepatology
PubMed ID25820364
PubMed Central IDPMC4482775
Grant ListP30 CA016087 / CA / NCI NIH HHS / United States
5P30CA016087-32 / CA / NCI NIH HHS / United States
R01 AI072613 / AI / NIAID NIH HHS / United States
R01 AI095098 / AI / NIAID NIH HHS / United States
1 R56 AI106005-01 / AI / NIAID NIH HHS / United States
5T32GM007388 / GM / NIGMS NIH HHS / United States
F32 AI091207 / AI / NIAID NIH HHS / United States
2R 01 AI079031-05A1 / AI / NIAID NIH HHS / United States
R01 DK085713 / DK / NIDDK NIH HHS / United States
R01 AI106005 / AI / NIAID NIH HHS / United States
R01 AI079031 / AI / NIAID NIH HHS / United States
R01 AI090055 / AI / NIAID NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 AI098485 / AI / NIAID NIH HHS / United States
5 R01 AI090055-05 / AI / NIAID NIH HHS / United States
R21 AI106000 / AI / NIAID NIH HHS / United States
K08 DK090576 / DK / NIDDK NIH HHS / United States
1 R01 DK085713-01 / DK / NIDDK NIH HHS / United States
R56 AI106005 / AI / NIAID NIH HHS / United States
R01 AI107301 / AI / NIAID NIH HHS / United States
5 R01 AI072613-08 / AI / NIAID NIH HHS / United States
1 R01 AI107301-01 / AI / NIAID NIH HHS / United States