Antibody–Selected Mimics of Hepatitis C Virus Hypervariable Region 1 Activate Both Primary and Memory Th Lymphocytes

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Abstract
An ideal strategy that leads to a vaccine aimed at controlling viral escape may be that of preventing the replication of escape mutants by eliciting a T– and B–cell repertoire directed against many viral variants. The hypervariable region 1 (HVR1) of the putative envelope 2 protein that presents B and T epitopes shown to induce protective immunity against hepatitis C virus (HCV), might be suitable for this purpose if its immunogenicity can be improved by generating mimics that induce broad, highly cross–reactive, anti–HVR1 responses. Recently we described a successful approach to select HVR1 mimics (mimotopes) incorporating the variability found in a great number of viral variants. In this report we explore whether these mimotopes, designed to mimic B–cell epitopes, also mimic helper T–cell epitopes. The first interesting observation is that mimotopes selected for their reactivity to HVR1–specific antibodies of infected patients also do express HVR1 T–cell epitopes, suggesting that similar constraints govern HVR1–specific humoral and cellular immune responses. Moreover, some HVR1 mimotopes stimulate a multispecific CD4+ T–cell repertoire that effectively cross–reacts with HVR1 native sequences. This may significantly limit effects as a T–cell receptor (TCR) antagonist frequently exerted by natural HVR1–variants on HVR1–specific T–cell responses. In conclusion, these data lend strong support to using HVR1 mimotopes in vaccines designed to prevent replication of escape mutants.

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