Tracking Virus-Specific CD4+ T Cells during and after Acute Hepatitis C Virus Infection
Identifieur interne : 002793 ( Pmc/Curation ); précédent : 002792; suivant : 002794Tracking Virus-Specific CD4+ T Cells during and after Acute Hepatitis C Virus Infection
Auteurs : Michaela Lucas [Royaume-Uni, Australie] ; Axel Ulsenheimer [Allemagne] ; Katja Pfafferot [Australie] ; Malte H. J. Heeg [Allemagne] ; Silvana Gaudieri [Australie] ; Norbert Grüner [Allemagne] ; Andri Rauch [Australie, Suisse] ; J. Tilman Gerlach [Allemagne] ; Maria-Christina Jung [Allemagne] ; Reinhart Zachoval [Allemagne] ; Gerd R. Pape [Allemagne] ; Winfried Schraut [Allemagne] ; Teresa Santantonio [Italie] ; Hans Nitschko [Allemagne] ; Martin Obermeier [Allemagne] ; Rodney Phillips [Royaume-Uni] ; Thomas J. Scriba [Royaume-Uni] ; Nasser Semmo [Royaume-Uni] ; Cheryl Day [Royaume-Uni] ; Jonathan N. Weber [Royaume-Uni] ; Sarah Fidler [Royaume-Uni] ; Robert Thimme [Allemagne] ; Anita Haberstroh [Allemagne] ; Thomas F. Baumert [France] ; Paul Klenerman [Royaume-Uni] ; Helmut M. Diepolder [Allemagne]Source :
- PLoS ONE [ 1932-6203 ] ; 2007.
Abstract
CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays.
Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C.
During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.
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DOI: 10.1371/journal.pone.0000649
PubMed: 17653276
PubMed Central: 1920556
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Weber</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Department of Medicine, Imperial College, St. Mary's Hospital, London, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medicine, Imperial College, St. Mary's Hospital, London</wicri:regionArea></affiliation></author><author><name sortKey="Fidler, Sarah" sort="Fidler, Sarah" uniqKey="Fidler S" first="Sarah" last="Fidler">Sarah Fidler</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Department of Medicine, Imperial College, St. Mary's Hospital, London, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medicine, Imperial College, St. Mary's Hospital, London</wicri:regionArea></affiliation></author><author><name sortKey="Thimme, Robert" sort="Thimme, Robert" uniqKey="Thimme R" first="Robert" last="Thimme">Robert Thimme</name><affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>Albert-Ludwigs-Universität, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Albert-Ludwigs-Universität, Freiburg</wicri:regionArea></affiliation></author><author><name sortKey="Haberstroh, Anita" sort="Haberstroh, Anita" uniqKey="Haberstroh A" first="Anita" last="Haberstroh">Anita Haberstroh</name><affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>Albert-Ludwigs-Universität, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Albert-Ludwigs-Universität, Freiburg</wicri:regionArea></affiliation></author><author><name sortKey="Baumert, Thomas F" sort="Baumert, Thomas F" uniqKey="Baumert T" first="Thomas F." last="Baumert">Thomas F. Baumert</name><affiliation wicri:level="1"><nlm:aff id="aff10"><addr-line>Inserm Unité 748, Université Louis Pasteur, Strasbourg, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm Unité 748, Université Louis Pasteur, Strasbourg</wicri:regionArea></affiliation></author><author><name sortKey="Klenerman, Paul" sort="Klenerman, Paul" uniqKey="Klenerman P" first="Paul" last="Klenerman">Paul Klenerman</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Diepolder, Helmut M" sort="Diepolder, Helmut M" uniqKey="Diepolder H" first="Helmut M." last="Diepolder">Helmut M. Diepolder</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">17653276</idno><idno type="pmc">1920556</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920556</idno><idno type="RBID">PMC:1920556</idno><idno type="doi">10.1371/journal.pone.0000649</idno><date when="2007">2007</date><idno type="wicri:Area/Pmc/Corpus">002943</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002943</idno><idno type="wicri:Area/Pmc/Curation">002793</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002793</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Tracking Virus-Specific CD4+ T Cells during and after Acute Hepatitis C Virus Infection</title><author><name sortKey="Lucas, Michaela" sort="Lucas, Michaela" uniqKey="Lucas M" first="Michaela" last="Lucas">Michaela Lucas</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth</wicri:regionArea></affiliation></author><author><name sortKey="Ulsenheimer, Axel" sort="Ulsenheimer, Axel" uniqKey="Ulsenheimer A" first="Axel" last="Ulsenheimer">Axel Ulsenheimer</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Pfafferot, Katja" sort="Pfafferot, Katja" uniqKey="Pfafferot K" first="Katja" last="Pfafferot">Katja Pfafferot</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth</wicri:regionArea></affiliation></author><author><name sortKey="Heeg, Malte H J" sort="Heeg, Malte H J" uniqKey="Heeg M" first="Malte H. J." last="Heeg">Malte H. J. Heeg</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Gaudieri, Silvana" sort="Gaudieri, Silvana" uniqKey="Gaudieri S" first="Silvana" last="Gaudieri">Silvana Gaudieri</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Centre for Forensic Science, School of Anatomy and Human Biology, University of Western Australia, Nedlands, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Forensic Science, School of Anatomy and Human Biology, University of Western Australia, Nedlands</wicri:regionArea></affiliation></author><author><name sortKey="Gruner, Norbert" sort="Gruner, Norbert" uniqKey="Gruner N" first="Norbert" last="Grüner">Norbert Grüner</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Rauch, Andri" sort="Rauch, Andri" uniqKey="Rauch A" first="Andri" last="Rauch">Andri Rauch</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Division of Infectious Diseases, University Hospital, Berne, Switzerland</addr-line></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Division of Infectious Diseases, University Hospital, Berne</wicri:regionArea></affiliation></author><author><name sortKey="Gerlach, J Tilman" sort="Gerlach, J Tilman" uniqKey="Gerlach J" first="J. Tilman" last="Gerlach">J. Tilman Gerlach</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Jung, Maria Christina" sort="Jung, Maria Christina" uniqKey="Jung M" first="Maria-Christina" last="Jung">Maria-Christina Jung</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Zachoval, Reinhart" sort="Zachoval, Reinhart" uniqKey="Zachoval R" first="Reinhart" last="Zachoval">Reinhart Zachoval</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Pape, Gerd R" sort="Pape, Gerd R" uniqKey="Pape G" first="Gerd R." last="Pape">Gerd R. Pape</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Schraut, Winfried" sort="Schraut, Winfried" uniqKey="Schraut W" first="Winfried" last="Schraut">Winfried Schraut</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Santantonio, Teresa" sort="Santantonio, Teresa" uniqKey="Santantonio T" first="Teresa" last="Santantonio">Teresa Santantonio</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Clinica delle Malattie Infettive, University of Bari, Bari, Italy</addr-line></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Clinica delle Malattie Infettive, University of Bari, Bari</wicri:regionArea></affiliation></author><author><name sortKey="Nitschko, Hans" sort="Nitschko, Hans" uniqKey="Nitschko H" first="Hans" last="Nitschko">Hans Nitschko</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Max von Pettenkofer-Institute, Department of Virology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max von Pettenkofer-Institute, Department of Virology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Obermeier, Martin" sort="Obermeier, Martin" uniqKey="Obermeier M" first="Martin" last="Obermeier">Martin Obermeier</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Max von Pettenkofer-Institute, Department of Virology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max von Pettenkofer-Institute, Department of Virology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Phillips, Rodney" sort="Phillips, Rodney" uniqKey="Phillips R" first="Rodney" last="Phillips">Rodney Phillips</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Scriba, Thomas J" sort="Scriba, Thomas J" uniqKey="Scriba T" first="Thomas J." last="Scriba">Thomas J. Scriba</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Semmo, Nasser" sort="Semmo, Nasser" uniqKey="Semmo N" first="Nasser" last="Semmo">Nasser Semmo</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Day, Cheryl" sort="Day, Cheryl" uniqKey="Day C" first="Cheryl" last="Day">Cheryl Day</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Weber, Jonathan N" sort="Weber, Jonathan N" uniqKey="Weber J" first="Jonathan N." last="Weber">Jonathan N. Weber</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Department of Medicine, Imperial College, St. Mary's Hospital, London, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medicine, Imperial College, St. Mary's Hospital, London</wicri:regionArea></affiliation></author><author><name sortKey="Fidler, Sarah" sort="Fidler, Sarah" uniqKey="Fidler S" first="Sarah" last="Fidler">Sarah Fidler</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Department of Medicine, Imperial College, St. Mary's Hospital, London, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medicine, Imperial College, St. Mary's Hospital, London</wicri:regionArea></affiliation></author><author><name sortKey="Thimme, Robert" sort="Thimme, Robert" uniqKey="Thimme R" first="Robert" last="Thimme">Robert Thimme</name><affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>Albert-Ludwigs-Universität, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Albert-Ludwigs-Universität, Freiburg</wicri:regionArea></affiliation></author><author><name sortKey="Haberstroh, Anita" sort="Haberstroh, Anita" uniqKey="Haberstroh A" first="Anita" last="Haberstroh">Anita Haberstroh</name><affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>Albert-Ludwigs-Universität, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Albert-Ludwigs-Universität, Freiburg</wicri:regionArea></affiliation></author><author><name sortKey="Baumert, Thomas F" sort="Baumert, Thomas F" uniqKey="Baumert T" first="Thomas F." last="Baumert">Thomas F. Baumert</name><affiliation wicri:level="1"><nlm:aff id="aff10"><addr-line>Inserm Unité 748, Université Louis Pasteur, Strasbourg, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Inserm Unité 748, Université Louis Pasteur, Strasbourg</wicri:regionArea></affiliation></author><author><name sortKey="Klenerman, Paul" sort="Klenerman, Paul" uniqKey="Klenerman P" first="Paul" last="Klenerman">Paul Klenerman</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Diepolder, Helmut M" sort="Diepolder, Helmut M" uniqKey="Diepolder H" first="Helmut M." last="Diepolder">Helmut M. Diepolder</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays.</p></sec><sec><title>Methodology/Principal Findings</title><p>Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C.</p></sec><sec><title>Conclusions/Significance</title><p>During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-title>PLoS ONE</journal-title><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name> <publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">17653276</article-id><article-id pub-id-type="pmc">1920556</article-id><article-id pub-id-type="publisher-id">07-PONE-RA-00840R2</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0000649</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline"><subject>Gastroenterology and Hepatology</subject><subject>Immunology/Immune Response</subject><subject>Immunology/Immunity to Infections</subject><subject>Infectious Diseases/Viral Infections</subject></subj-group></article-categories><title-group><article-title>Tracking Virus-Specific CD4+ T Cells during and after Acute Hepatitis C Virus Infection</article-title><alt-title alt-title-type="running-head">HCV Specific CD4+ T Cells</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Lucas</surname><given-names>Michaela</given-names></name><xref rid="aff1" ref-type="aff"><sup>1</sup></xref><xref rid="aff3" ref-type="aff"><sup>3</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Ulsenheimer</surname><given-names>Axel</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pfafferot</surname><given-names>Katja</given-names></name><xref rid="aff3" ref-type="aff"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Heeg</surname><given-names>Malte H.J.</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gaudieri</surname><given-names>Silvana</given-names></name><xref rid="aff3" ref-type="aff"><sup>3</sup></xref><xref rid="aff4" ref-type="aff"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Grüner</surname><given-names>Norbert</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rauch</surname><given-names>Andri</given-names></name><xref rid="aff3" ref-type="aff"><sup>3</sup></xref><xref rid="aff5" ref-type="aff"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gerlach</surname><given-names>J. Tilman</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jung</surname><given-names>Maria-Christina</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zachoval</surname><given-names>Reinhart</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pape</surname><given-names>Gerd R.</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schraut</surname><given-names>Winfried</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Santantonio</surname><given-names>Teresa</given-names></name><xref rid="aff6" ref-type="aff"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nitschko</surname><given-names>Hans</given-names></name><xref rid="aff7" ref-type="aff"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Obermeier</surname><given-names>Martin</given-names></name><xref rid="aff7" ref-type="aff"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Phillips</surname><given-names>Rodney</given-names></name><xref rid="aff1" ref-type="aff"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Scriba</surname><given-names>Thomas J.</given-names></name><xref rid="aff1" ref-type="aff"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Semmo</surname><given-names>Nasser</given-names></name><xref rid="aff1" ref-type="aff"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Day</surname><given-names>Cheryl</given-names></name><xref rid="aff1" ref-type="aff"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Weber</surname><given-names>Jonathan N.</given-names></name><xref rid="aff8" ref-type="aff"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fidler</surname><given-names>Sarah</given-names></name><xref rid="aff8" ref-type="aff"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Thimme</surname><given-names>Robert</given-names></name><xref rid="aff9" ref-type="aff"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haberstroh</surname><given-names>Anita</given-names></name><xref rid="aff9" ref-type="aff"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Baumert</surname><given-names>Thomas F.</given-names></name><xref rid="aff10" ref-type="aff"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Klenerman</surname><given-names>Paul</given-names></name><xref rid="aff1" ref-type="aff"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Diepolder</surname><given-names>Helmut M.</given-names></name><xref rid="aff2" ref-type="aff"><sup>2</sup></xref><xref ref-type="corresp" rid="n101"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Medical Department II and Institute for Immunology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Australia</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Centre for Forensic Science, School of Anatomy and Human Biology, University of Western Australia, Nedlands, Australia</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Division of Infectious Diseases, University Hospital, Berne, Switzerland</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Clinica delle Malattie Infettive, University of Bari, Bari, Italy</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Max von Pettenkofer-Institute, Department of Virology, Ludwig-Maximilians-University Munich, Munich, Germany</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Department of Medicine, Imperial College, St. Mary's Hospital, London, United Kingdom</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Albert-Ludwigs-Universität, Freiburg, Germany</addr-line></aff><aff id="aff10"><label>10</label><addr-line>Inserm Unité 748, Université Louis Pasteur, Strasbourg, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Bowyer</surname><given-names>Sheila</given-names></name><role>Academic Editor</role><xref rid="edit1" ref-type="aff"></xref></contrib></contrib-group><aff id="edit1">National Institute for Communicable Diseases, South Africa</aff><author-notes><corresp id="n101">* To whom correspondence should be addressed. E-mail: <email>hdiepold@med.uni-muenchen.de</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: RP ML PK HD AU GP. Performed the experiments: ML RT PK AU KP MH SG AR HN MO AH. Analyzed the data: ML RT NS TS CD HD TB AU KP SG NG MJ GP HN MO AH WS. Contributed reagents/materials/analysis tools: RP PK JW NS SF TS CD TB NG MJ RZ TS TG WS. Wrote the paper: HD. Other: Conceived and designed the study: MD. Enrolled patients: MD. Wrote the first draft of the paper: HD.</p></fn></author-notes><pub-date pub-type="collection"><year>2007</year></pub-date><pub-date pub-type="epub"><day>25</day><month>7</month><year>2007</year></pub-date><volume>2</volume><issue>7</issue><elocation-id>e649</elocation-id><history><date date-type="received"><day>28</day><month>2</month><year>2007</year></date><date date-type="accepted"><day>18</day><month>6</month><year>2007</year></date></history><copyright-statement>Lucas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</copyright-statement><copyright-year>2007</copyright-year><abstract><sec><title>Background</title><p>CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays.</p></sec><sec><title>Methodology/Principal Findings</title><p>Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C.</p></sec><sec><title>Conclusions/Significance</title><p>During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1+ patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists.</p></sec></abstract><counts><page-count count="11"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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