Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence.
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.
Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Julian
J
Schulze Zur Wiesch
Donatella
D
Ciuffreda
Lia
L
Lewis-Ximenez
Victoria
V
Kasprowicz
Brian E
BE
Nolan
Hendrik
H
Streeck
Jasneet
J
Aneja
Laura L
LL
Reyor
Todd M
TM
Allen
Ansgar W
AW
Lohse
Barbara
B
McGovern
Raymond T
RT
Chung
William W
WW
Kwok
Arthur Y
AY
Kim
Georg M
GM
Lauer
D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology; D000998:Antiviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012075:Remission, Spontaneous; D014766:Viremia / Q000276:immunology; D055815:Young Adult
D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2