Emergence of a distinct pattern of viral mutations in chimpanzees infected with a homogeneous inoculum of hepatitis C virus.
OBJECTIVE
Prospective, long-term study of viral evolution and immunologic responses in chimpanzees infected with a homogeneous hepatitis C virus (HCV) population is crucial in understanding the pathogenesis of HCV-host interactions.


METHODS
A molecular clone was constructed of HCV genotype 1b and RNA transcribed from this clone inoculated intrahepatically into chimpanzee X0142. Serum was taken from X0142 at week 2 and inoculated intravenously into a second chimpanzee (X0234). Detailed virologic, serologic, and immunologic analyses of these 2 chimpanzees were performed.


RESULTS
Both chimpanzees developed persistent viremia, with titers of 10(3) to 10(5) genomes/mL, for 80 weeks (X0142) and 55 weeks (X0234) of follow-up. A late antibody response against the nonstructural proteins and a weak, transient T-helper proliferative response were detected in both animals. In X0142, 25 mutations emerged in the virus population by week 78 and 15 in X0234 by week 35. A relatively large proportion of mutations affecting protein sequences appeared in the NS5A gene (33% in X0142 and X0234 combined), and 5 mutations were common to both chimpanzees.


CONCLUSIONS
In this long-term study of the molecular evolution of HCV genotype 1b from a cloned source, the appearance of a distinct pattern of mutations is suggestive of an adaptive response of HCV in vivo. In addition, a limited virus-specific immunity may contribute to HCV persistence.
Thomson
M
M
Liver Diseases Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1800, USA.
Nascimbeni
M
M
Gonzales
S
S
Murthy
K K
KK
Rehermann
B
B
Liang
T J
TJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000302:isolation & purification; D004279:DNA, Viral / Q000235:genetics; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D002679:Pan troglodytes; D012367:RNA, Viral / Q000097:blood; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D000410:Alanine Transaminase; D018076:DNA, Complementary; D004279:DNA, Viral; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase