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T Cell Recognition of Hypervariable Region-1 from Hepatitis C Virus Envelope Protein with Multiple Class II MHC Molecules in Mice and Humans: Preferential Help for Induction of Antibodies to the Hypervariable Region¹

Mutsunori Shirai^2,*,, Tatsumi Arichi^2,,, Ming Chen, Mikio Nishioka, Kazumasa Ikeda^§, Hidemi Takahashi^¶, Nobuyuki Enomoto^||, Takafumi Saito^#, Marian E. Major^#, Teruko Nakazawa^*, Toshitaka Akatsuka^#, Stephen M. Feinstone^# and Jay A. Berzofsky^3,

^* Department of Microbiology, Yamaguchi University School of Medicine, Yamaguchi, Japan; Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Third Department of Internal Medicine and ^§ Department of Transfusion Medicine, Kagawa Medical School, Kagawa, Japan; ^¶ Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan; ^|| Second Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo, Japan; and ^# Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Hypervariable region-1 (HVR1) from the hepatitis C virus (HCV) envelope protein is thought to be a target for neutralizing Abs. To explore HVR1 recognition by helper T cells, and their role in Ab responses, we attempted to generate helper T cells specific for HVR1 in mice of three MHC types, and with PBMC from HCV-infected HLA-diverse humans. In both species, HVR1 was presented by >1 class II MHC molecule to CD4⁺ helper T cells and showed surprising interisolate cross-reactivity. The epitope for two DR4⁺ patients was mapped to a more conserved C-terminal sequence containing a DR4 binding motif, possibly accounting for cross-reactivity. Strikingly, Abs to patients’ own HVR1 sequences were found only in patients with T cell responses to HVR1, even though all had Abs to envelope protein, suggesting that induction of Abs to HVR1 depends on helper T cells specific for a sequence proximal to the Ab epitope. Thus, helper T cells specific for HVR1 may be functionally important in inducing neutralizing Abs to HCV. These results may be the first example of "T-B reciprocity," in which proximity of a helper T cell epitope determines Ab epitope specificity, in a human disease setting.

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