Hepatitis C virus (HCV)-specific CD8 cell exhaustion may represent a mechanism of HCV persistence. The inhibitory receptor PD-1 has been reported to be up-regulated in exhausted CD8 cells. Therefore, we studied PD-1 expression longitudinally during acute HCV infection. Most HCV-specific CD8 cells expressed PD-1 at the time of acute illness, irrespective of the final outcome. PD-1 expression declined with the acquisition of a memory phenotype and recovery of an efficient CD8 cell function in resolving HCV infections, whereas high levels were maintained when HCV persisted and HCV-specific CD8 cells remained dysfunctional. Blocking PD-1/PDL-1 interaction with an anti-PDL-1 antibody improved the capacity of expansion of virus-specific CD8 cells.

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 ␥, interleukin ( S pontaneous clearance of hepatitis C virus infection occurs in a small percentage of acutely infected patients and is associated with a vigorous cellular immune response of a broad specificity. [1][2][3][4][5][6][7][8][9] In contrast, chronic infection is characterized by less vigorous and narrowly focused CD4 and CD8 T cell responses. The mechanisms responsible for immune failure in patients who do not succeed in clearing the virus spontaneously are still unclear. Although there have been several reports of the hepatitis C virus (HCV)-specific cellular immune response during acute illness, a comprehensive study analyzing simultaneously the contribution of each T cell subsets to the mechanisms of clearance or persistence has never been performed. Most recent reports used wide panels of 10-to 15-mer HCV peptides that cannot distinguish the relative contribution of CD4 and CD8 cells to the overall antiviral T cell response. [5][6][7][8][9][10][11] Alternatively, a small number of preselected epitopes of known HLA restriction or whole recombinant HCV proteins were tested. [12][13][14][15][16][17][18] Moreover, only limited information is available about the ex vivo profile of cytokine production in the acute phase of infection, because ELISPOT and intracellular cytokine staining (ICS) analysis were based on the measure of interferon-␥ (IFN-␥) only. 12,19 In the present study, we used panels of genotypematched, overlapping peptides covering the entire HCV sequence to obtain a reliable representation of the overall T cell response to HCV, associated with control of infec-

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