Article

Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

Laboratory of Viral Immunopathology, Department of Infectious Diseases and Hepatology, Azienda Ospedaliera di Parma, Parma, Italy.
Hepatology (Impact Factor: 11.19). 07/2006; 44(1):126-39. DOI: 10.1002/hep.21242
Source: PubMed

ABSTRACT A timely, efficient, and coordinated activation of both CD4 and CD8 T cell subsets following HCV infection is believed to be essential for HCV control. However, to what extent a failure of the individual T cell subsets can contribute to the high propensity of HCV to persist is still largely undefined. To address this issue, we analyzed the breadth, vigor, and quality of CD4 and CD8 responses simultaneously with panels of peptides covering the entire HCV sequence or containing the HLA-A2-binding motif, and with recombinant HCV proteins in 16 patients with acute HCV infection by tetramer staining, ELISPOT, and intracellular cytokine staining for interferon gamma, interleukin (IL)-2, IL-4, and IL-10. Our results indicate that at clinical onset, CD8 responses are similarly weak and narrowly focused in both self-limited and chronically evolving infections. At this stage, CD4 responses are deeply impaired in patients with a chronic outcome as they are weak and of narrow specificity, unlike the strong, broad and T helper 1-oriented CD4 responses associated with resolving infections. Only patients able to finally control infection show maturation of CD8 memory sustained by progressive expansion of CD127+ CD8 cells. Thus, a poor CD8 response in the acute stage of infection may enhance the overall probability of chronic viral persistence. In conclusion, the presence of functional CD4 responses represents one of the factors dictating the fate of infection by directly contributing to control of the virus and by promoting maturation of protective memory CD8 responses.

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    • "Despite the plethora of studies on CD8 T cells, it is still not entirely clear what kind of CD8 T cell response is required to achieve full control of HCV. Again, as with CD4 responses, vigorous and broadly directed CD8 responses were observed in self-limited disease [17] [28], but if individuals were studied within the initial 6 months of HCV infection, similarly strong CD8 responses could be seen in patients with a chronic course of infection [22]. What we understand better, compared to the CD4 responses, are the different mechanisms that render the HCV-specific CD8 T cell response debilitated and unable to control the virus throughout the progression to persistent viraemia. "
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    • "Typically, patients with self-limited acute HCV infection undergo sustained viral clearance within the first 12 weeks of disease onset, whereas viremia beyond 6 months generally indicates chronic evolution (4). The divergent outcomes of acute HCV infection are known to be determined by differences in virus-specific T-cell responses among patients (5–9). "
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    • "However, due to the very low frequency of circulating HBV- and HCV-specific CD4+ T cells, very little is known about the exact differentiation and function of these cells. Taken together, HBV- and HCV-specific CD4+ T cells do not seem to primarily mediate direct antiviral effects, but play an important role for the clearance of the virus by enhancing the effector responses of virus-specific CD8+ T cells.23,40,41 "
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