Previously infected chimpanzees are not consistently protected against reinfection or persistent infection after reexposure to the identical hepatitis C virus strain.
Protective immunity after resolved hepatitis C virus (HCV) infection has been reported. However, the breadth of this immunity has remained controversial, and the role of neutralizing antibodies has not been well-defined. In the present study, two chimpanzees (CH96A008 and CH1494) with resolved monoclonal H77C (genotype 1a) infection were rechallenged with low-dose homologous H77C virus about 12 months after viral clearance; CH96A008 became persistently infected, and CH1494 had transient viremia lasting 2 weeks. CH1494 was subsequently either partially or completely protected following five homologous rechallenges with monoclonal H77C or polyclonal H77 and after six heterologous rechallenges with HC-J4 (genotype 1b) or HC-J6 (genotype 2a) viruses. Subsequently, a final challenge with H77C resulted in persistent HCV infection. In both chimpanzees, serum neutralizing antibodies against retroviral pseudoparticles bearing the H77C envelope proteins were not detected during the initial infection or during rechallenge. However, anamnestic cellular immune responses developed during the initial homologous rechallenge, in particular in CH96A008, which developed a persistent infection. Polyprotein sequences of viruses recovered from CH1494 after the two homologous rechallenges that resulted in transient viremia were identical with the H77C virus. In contrast, the polyprotein sequences of viruses recovered from both chimpanzees after homologous rechallenge resulting in persistent infection had numerous changes. These findings have important implications for our understanding of immunity against HCV; even in the best-case scenario with autologous rechallenge, low-level viral persistence was seen in the presence of primed T-cell responses.
Hepatitis Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 50, Room 6531, 50 South Dr., MSC 8009, Bethesda, MD 20892-8009, USA. jbukh@niaid.nih.gov
Jens
J
Bukh
Robert
R
Thimme
Jean-Christophe
JC
Meunier
Kristina
K
Faulk
Hans Christian
HC
Spangenberg
Kyong-Mi
KM
Chang
William
W
Satterfield
Francis V
FV
Chisari
Robert H
RH
Purcell
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology*; D007107:Immune System; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D009711:Nucleotides / Q000737:chemistry; D016366:Open Reading Frames; D002679:Pan troglodytes; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology
D009711:Nucleotides