Challenge pools of hepatitis C virus genotypes 1-6 prototype strains: replication fitness and pathogenicity in chimpanzees and human liver-chimeric mouse models.
Chimpanzees represent the only animal model for studies of the natural history of hepatitis C virus (HCV). To generate virus stocks of important HCV variants, we infected chimpanzees with HCV strains of genotypes 1-6 and determined the infectivity titer of acute-phase plasma pools in additional animals. The courses of first- and second-passage infections were similar, with early appearance of viremia, HCV RNA titers of >10(4.7) IU/mL, and development of acute hepatitis; the chronicity rate was 56%. The challenge pools had titers of 10(3)-10(5) chimpanzee infectious doses/mL. Human liver-chimeric mice developed high-titer infections after inoculation with the challenge viruses of genotypes 1-6. Inoculation studies with different doses of the genotype 1b pool suggested that a relatively high virus dose is required to consistently infect chimeric mice. The challenge pools represent a unique resource for studies of HCV molecular virology and for studies of pathogenesis, protective immunity, and vaccine efficacy in vivo.
Bukh
Jens
J
Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg 50, 50 S Dr MSC 8009, Bethesda, MD 20892-8009, USA. jbukh@niaid.nih.gov
Meuleman
Philip
P
Tellier
Raymond
R
Engle
Ronald E
RE
Feinstone
Stephen M
SM
Eder
Gerald
G
Satterfield
William C
WC
Govindarajan
Sugantha
S
Krawczynski
Krzysztof
K
Miller
Roger H
RH
Leroux-Roels
Geert
G
Purcell
Robert H
RH
D000818:Animals; D002478:Cells, Cultured; D002678:Chimera / Q000821:virology; D004195:Disease Models, Animal; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity*; D006526:Hepatitis C / Q000821:virology; D006801:Humans; D008099:Liver / Q000821:virology*; D051379:Mice; D016513:Mice, SCID / Q000821:virology; D002679:Pan troglodytes / Q000821:virology