Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence.
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Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. / Schulze Zur Wiesch, Julian; Ciuffreda, Donatella; Lewis-Ximenez, Lia; Kasprowicz, Victoria; Nolan, Brian E; Streeck, Hendrik; Aneja, Jasneet; Reyor, Laura L; Allen, Todd M; Lohse, Ansgar W.; McGovern, Barbara; Chung, Raymond T; Kwok, William W; Kim, Arthur Y; Lauer, Georg M.
in: J EXP MED, Jahrgang 209, Nr. 1, 1, 2012, S. 61-75.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence.
AU - Schulze Zur Wiesch, Julian
AU - Ciuffreda, Donatella
AU - Lewis-Ximenez, Lia
AU - Kasprowicz, Victoria
AU - Nolan, Brian E
AU - Streeck, Hendrik
AU - Aneja, Jasneet
AU - Reyor, Laura L
AU - Allen, Todd M
AU - Lohse, Ansgar W.
AU - McGovern, Barbara
AU - Chung, Raymond T
AU - Kwok, William W
AU - Kim, Arthur Y
AU - Lauer, Georg M
PY - 2012
Y1 - 2012
N2 - Vigorous proliferative CD4(+) T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4(+) T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4(+) T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4(+) T cells, followed by rapid deletion of the HCV-specific response. Only early initiation of antiviral therapy was able to preserve CD4(+) T cell responses in acute, chronically evolving infection. Our results challenge the paradigm that HCV persistence is the result of a failure to prime HCV-specific CD4(+) T cells. Instead, broadly directed HCV-specific CD4(+) T cell responses are usually generated, but rapid exhaustion and deletion of these cells occurs in the majority of patients. The data further suggest a short window of opportunity to prevent the loss of CD4(+) T cell responses through antiviral therapy.
AB - Vigorous proliferative CD4(+) T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4(+) T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4(+) T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4(+) T cells, followed by rapid deletion of the HCV-specific response. Only early initiation of antiviral therapy was able to preserve CD4(+) T cell responses in acute, chronically evolving infection. Our results challenge the paradigm that HCV persistence is the result of a failure to prime HCV-specific CD4(+) T cells. Instead, broadly directed HCV-specific CD4(+) T cell responses are usually generated, but rapid exhaustion and deletion of these cells occurs in the majority of patients. The data further suggest a short window of opportunity to prevent the loss of CD4(+) T cell responses through antiviral therapy.
KW - Adult
KW - Humans
KW - Male
KW - Female
KW - Middle Aged
KW - Young Adult
KW - Cohort Studies
KW - Cell Proliferation/drug effects
KW - Remission, Spontaneous
KW - Histocompatibility Antigens Class II/immunology
KW - Antiviral Agents/therapeutic use
KW - Epitopes, T-Lymphocyte/immunology
KW - Lymphocyte Activation/drug effects/immunology
KW - Antibodies, Neutralizing/immunology
KW - CD4-Positive T-Lymphocytes/drug effects/immunology
KW - Hepacivirus/immunology
KW - Hepatitis C/drug therapy/immunology/virology
KW - Interleukin-2/immunology/pharmacology
KW - Viremia/immunology
KW - Adult
KW - Humans
KW - Male
KW - Female
KW - Middle Aged
KW - Young Adult
KW - Cohort Studies
KW - Cell Proliferation/drug effects
KW - Remission, Spontaneous
KW - Histocompatibility Antigens Class II/immunology
KW - Antiviral Agents/therapeutic use
KW - Epitopes, T-Lymphocyte/immunology
KW - Lymphocyte Activation/drug effects/immunology
KW - Antibodies, Neutralizing/immunology
KW - CD4-Positive T-Lymphocytes/drug effects/immunology
KW - Hepacivirus/immunology
KW - Hepatitis C/drug therapy/immunology/virology
KW - Interleukin-2/immunology/pharmacology
KW - Viremia/immunology
M3 - SCORING: Journal article
VL - 209
SP - 61
EP - 75
JO - J EXP MED
JF - J EXP MED
SN - 0022-1007
IS - 1
M1 - 1
ER -
