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

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 ␥, 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-

Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis

“…HCV-specific Tr1 response was also detected regardless of subsequent virological outcome in our study, similar to Urbani et al (47). However, in the present study the strength of HCV-specific Tr1 response (but not IFNγ response) correlated with clinical, virological and immunological parameters during acute infection.…”

“…While antigen-specific Tr1 response has been detected in patients with acute and chronic hepatitis C (13,34,47,48), this response begins early within 1-2 months of acute clinical hepatitis in our subjects, contrasting their detection only after 24 weeks of infection in a study of genotype 4 infection(48). HCV-specific Tr1 response was also detected regardless of subsequent virological outcome in our study, similar to Urbani et al (47).…”

Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity

“…Indeed, impairment of adaptive immune responses in the presence of HCV infection in humans has been reported at both the level of dendritic and T helper cells. [44][45][46][47] Recently, several studies have reported that T helper dependent CD8 ϩ T cell effector function is reduced in HCV infection (reduced proliferation, perforin and IFN-␥ expression), similar to observations in HIV infected individuals. [48][49][50][51][52] In addition, whereas strong HCV specific humoral and CD4 ϩ T cell responses were induced in all vaccinees, vaccine-induced CD8 ϩ T cell responses detected by intracellular cytokine staining were rather weak in 3 of the 4 vaccinees.…”

Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection

“…[4][5][6] Thus, circulating HCV-specific CD8 T lymphocytes appear to be dysfunctional memory cells that can be variably rescued in their function by in vitro PD-1/PD-L1 blockade. This CD8 phenotype of long-term chronic HCV infections differs from the CD8 phenotype observed early after acute infection, 27,28 when HCV-specific CD8 cells in chronically evolving infections are highly PD-1 positive but predominantly CD127 negative. A continuous priming and recruitment of new thymic emigrants has been suggested to contribute to the maintenance of the virus-specific CD8 population in longlasting chronic viral infections.…”

“…12,18,[19][20][21][22][23][24][25][26][27][28] Although readily detectable in the acute stage of infection, HCVspecific CD8 responses are difficult to analyze in chronic hepatitis C because of the low peripheral blood CD8 cell frequency at this stage of infection. 29,30 Frequency is greater within the infected liver, but the number of HCVspecific CD8 cells that can be isolated from a liver biopsy specimen is too limited to allow comprehensive ex vivo functional studies.…”