CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus

Abstract

Hepatitis C is a major cause of chronic liver disease, with 170 million individuals infected worldwide and no available vaccine. We analyzed the effects of an induced T-cell response in 3 chimpanzees, targeting nonstructural proteins in the absence of neutralizing antibodies. In all animals the specific T-cell response modified the outcome of infection, producing a 10-to 1,000-fold reduction in peak virus titers. The challenge of 2 immunized animals that had been previously exposed to hepatitis C virus resulted in subclinical infections. Immune responses in the third animal, naive prior to immunization, limited viral replication immediately, evidenced by a 30-fold reduction in virus titer by week 2, declining to a nonquantifiable level by week 6. After 10 weeks of immunological control, we observed a resurgence P ersistent infections caused by hepatitis C virus (HCV) occur in 70%-80% of the acutely infected population, most of whom will develop chronic hepatitis and be at risk for cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma. 1 Antiviral therapy at present is successful in about 50% of patients, but treatment carries significant side effects and is very costly. 2,3 At present, about 25,000 new HCV infections occur each year in the United States, making the development of a vaccine against this virus imperative.Natural infection with HCV had previously been thought to afford no protective immunity from reinfection. 4,5 However, we and others have shown that following rechallenge, viremia and liver disease are significantly reduced in both intensity and duration 6-8 ; this appears to be mediated through faster T-cell activation in peripheral blood and liver in chimpanzees 8,9 and possibly in humans. 10 Despite developments with transgenic mouse systems using transplanted human hepatocytes, 11 the only established animal model for HCV is the chimpanzee, 12 which makes challenge vaccine experiments difficult and expensive. The development of HCV vaccines has also been hampered by the lack of an effective in vitro cell culture

Sequence diversity of hepatitis C virus: Implications for immune control and therapy

“…More recently, two studies have described mutational escape from CD4 responses. The first report is part of a vaccination study in the chimpanzee model [71] . One animal was vaccinated with DNA followed by recombinant vaccinia virus in a prime/boost strategy with HCV NS3 and NS5A/B and subsequently infected with a genotype 1a isolate.…”

Virus-Specific T-Cell Immunity Correlates with Control of GB Virus B Infection in Marmosets

“…The chimpanzee is the only animal model that supports virus replication and has been used in studies examining vaccine efficacy (12,26), but due to the high cost involved in their enrollment and care and their endangered status, these animals are beyond the reach of most research groups. Consequently, protective or immunosuppressive regions of the HCV polyprotein that should be incorporated into or excluded from vaccine design are still unknown.…”

Three-Dimensional Structure Determines the Pattern of CD4+T-Cell Epitope Dominance in Influenza Virus Hemagglutinin

“…The importance of specific CD4 ϩ responses in protection against other viruses is evident in the appearance of immune escape mutations. Mutation of a CD4 ϩ epitope was shown to be a viable mechanism for immune escape by lymphocytic choriomeningitis virus in mice (11), and CD4 ϩ escape mutants have been described in chronic hepatitis C virus (HCV) infections (53,69,70). Some human immunodeficiency virus (HIV) mutations whose selection cannot be explained by escape from CD8 ϩ T cells are located in CD4 ϩ epitopes (3).…”