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Escaping High Viral Load Exhaustion : CD8 Cells with Altered Tetramer Binding in Chronic Hepatitis B Virus Infection

Stephanie Reignat¹, George J.M. Webster², David Brown², Graham S. Ogg³, Abigail King³, Suranjith L. Seneviratne³, Geoff Dusheiko², Roger Williams¹, Mala K. Maini¹ and Antonio Bertoletti¹

¹ Institute of Hepatology, University College London, London WC1 E6HX, United Kingdom
² Centre for Hepatology, Royal Free Campus, Royal Free and University College Medical School, London NW3 2QG, United Kingdom
³ Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom

Address correspondence to Antonio Bertoletti, Institute of Hepatology, University College London 69-75, Chenies Mews, London WC1 E6HX, UK. Phone: 44-20-7679 6517; Fax: 44-20-7679 0405; E-mail: a.bertoletti{at}ucl.ac.uk

Deletion, anergy, and a spectrum of functional impairments can affect virus-specific CD8 cells in chronic viral infections. Here we characterize a low frequency population of CD8 cells present in chronic hepatitis B virus (HBV) infection which survive in the face of a high quantity of viral antigen. Although they do not appear to exert immunological pressure in vivo, these CD8 cells are not classically "tolerant" since they proliferate, lyse, and produce antiviral cytokines in vitro. They are characterized by altered HLA/peptide tetramer reactivity, which is not explained by TCR down-regulation or reduced functional avidity and which can be reversed with repetitive stimulation. CD8 cells with altered tetramer binding appear to have a specificity restricted to envelope antigen and not to other HBV antigens, suggesting that mechanisms of CD8 cell dysfunction are differentially regulated according to the antigenic form and presentation of individual viral antigens.

Key Words: cytotoxic T lymphocytes • chronic hepatitis B • viral diseases • immune tolerance • viral T antigen

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