Previously Infected Chimpanzees Are Not Consistently Protected against Reinfection or Persistent Infection after Reexposure to the Identical Hepatitis C Virus Strain

Abstract

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.

Enhanced and Sustained CD8+ T Cell Responses with an Adenoviral Vector-Based Hepatitis C Virus Vaccine Encoding NS3 Linked to the MHC Class II Chaperone Protein Invariant Chain

“…In addition, the importance of both CD4 + and CD8 + memory T cells for protection against persistent HCV infection has been demonstrated by depletion studies performed in experimentally infected chimpanzees (10,11). The significance of the cellular immune response is further underscored by the fact that experimentally infected chimpanzees were found to be protected against repeated rechallenges in the absence of neutralizing Abs (12). Studies of other chronic viral infections indicate that, in addition to the frequency and specificity of the CD4 + and CD8 + T cells, the ability of the virusspecific memory cells to simultaneously produce multiple antiviral cytokines (IFN-g, TNF-a, and IL-2) might be associated with good viral control (13)(14)(15).…”

Systematic review of chimpanzee use in monoclonal antibody research and drug development: 1981-2010

“…the type of biopsy (such as needle, laparoscopic, or surgical biopsy) was usually not specified. In the case of long-running studies (Goncalvez et al, 2008), a chimpanzee might be subjected to dozens of liver biopsies or other tissue biopsies (Bukh et al, 2008).…”

“…HIV and hepatitis were by far the most frequent pathogens used in this manner (Wang et al, 1999;Bukh et al, 2008). Others included smallpox, Dengue fever, anthrax, human t-cell lymphoma virus (HtlV), herpes, respiratory syncytial virus, tuberculosis, encephalitis, and malaria (Chen et al, 2006a,b;Men et al, 2004;Arp et al, 1996;Blewett et al, 1999;Crowe et al, 1994;Franzoso et al, 1993;Goncalvez et al, 2008;Klotz et al, 1996).…”

Experimental models to study the immunobiology of hepatitis C virus

“…Studies in reinfected chimpanzees that previously cleared the infection have revealed the existence of a protective immunity, which may, however, not be able to consistently prevent reinfection (Bukh et al, 2008;Major et al, 2002). The protection seems to be T-cell-mediated (reviewed by Bowen & Walker, 2005).…”

“…Interestingly, humoral immunity does not seem to be associated with HCV clearance in chimpanzees (Bartosch et al, 2003;Bukh et al, 2008;Cooper et al, 1999;Major et al, 1999Major et al, , 2004Thimme et al, 2002). One possible explanation is that titres of anti-hypervariable region 1 (HVR1) antibody, an antibody to the critical neutralization domain of E2 protein (Farci et al, 1996), do not correlate well with titres of HCV-specific neutralizing antibodies in vivo (Bartosch et al, 2003;Major et al, 1999).…”