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Tracking of Peptide-Specific CD4⁺ T-Cell Responses after an Acute Resolving Viral Infection: a Study of Parvovirus B19

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom,¹ Division of Clinical Virology, Karolinska Institute, Stockholm, Sweden,² Department of Virology, John Radcliffe Hospital, Oxford University,³ Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom⁴

Received 6 June 2006/ Accepted 21 August 2006

The evolution of peptide-specific CD4⁺ T-cell responses to acute viral infections of humans is poorly understood. We analyzed the response to parvovirus B19 (B19), a ubiquitous and clinically significant pathogen with a compact and conserved genome. The magnitude and breadth of the CD4⁺ T-cell response to the two B19 capsid proteins were investigated using a set of overlapping peptides and gamma interferon-specific enzyme-linked immunospot assays of peripheral blood mononuclear cells (PBMCs) from a cohort of acutely infected individuals who presented with acute arthropathy. These were compared to those for a cohort of B19-specific immunoglobulin M-negative (IgM^–), IgG⁺ remotely infected individuals. Both cohorts of individuals were found to make broad CD4⁺ responses. However, while the responses following acute infection were detectable ex vivo, responses in remotely infected individuals were only detected after culture. One epitope (LASEESAFYVLEHSSFQLLG) was consistently targeted by both acutely (10/12) and remotely (6/7) infected individuals. This epitope was DRB1*1501 restricted, and a major histocompatibility complex peptide tetramer stained PBMCs from acutely infected individuals in the range of 0.003 to 0.042% of CD4⁺ T cells. Tetramer-positive populations were initially CD62L^lo; unlike the case for B19-specific CD8⁺ T-cell responses, however, CD62L was reexpressed at later times, as responses remained stable or declined slowly. This first identification of B19 CD4⁺ T-cell epitopes, including a key immunodominant peptide, provides the tools to investigate the breadth, frequency, and functions of cellular responses to this virus in a range of specific clinical settings and gives an important reference point for analysis of peptide-specific CD4⁺ T cells during acute and persistent virus infections of humans.

Published ahead of print on 30 August 2006.