More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus-host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies.
The cellular immune response contributes to clearance of hepatitis C virus (HCV) and persists for decades after recovery from infection. The immunological basis for the inefficiency of the cellular immune response in chronically infected persons is not known. Here, we used four HLA-A2 tetramers, specific for two HCV core and two HCV NS3 epitopes, to investigate at the single-cell level effector function and phenotype of HCV-specific CD8+ T cells in 20 chronically infected and 12 long-term recovered patients. Overall, HCV-specific, tetramer+ T cells were more frequently found in PBMCs of chronically infected patients than in those of recovered patients. However, when compared with HCV-tetramer+ T cells of recovered patients, they displayed an impaired proliferative capacity. As a result of the impaired proliferative capacity, HCV-specific T cell lines derived from chronically infected patients displayed less peptide-specific cytotoxicity than those from recovered patients. In addition, proliferation and ex vivo IFN-γ production of HCV-tetramer+ cells, but not influenza-virus-specific T cells, were defective in chronically infected patients and could not be restored by in vitro stimulation with peptide and IL-2. At least three distinct phenotypes of HCV-specific CD8+ T cells were identified and associated with certain functional characteristics. In addition, impairment of proliferative, cytokine, and cytotoxic effector functions of tetramer+ T cells in viremic patients was associated with weak ex vivo HCV-specific CD4+ T cell responses. Thus, the defective functions of HCV-specific CD8+ T cells might contribute to viral persistence in chronically infected patients, and knowledge on their reversibility may facilitate the development of immunotherapeutic vaccines.
IntroductionT-cell development is an ordered process thought to take place exclusively in the thymus where CD4 ϩ CD8 ϩ T cells develop into CD4 ϩ and CD8 ϩ T cells with mutually exclusive expression of these 2 receptors. Mature CD4 ϩ and CD8 ϩ T cells then leave the thymus and enter secondary lymphoid organs where they recognize their cognate antigen in the context of major histocompatibility complex (MHC) class II and class I molecules on antigenpresenting cells. Antigenic stimulation induces proliferation and differentiation into armed effector cells with the ability to home to infected organs and to participate in immune responses against intracellular pathogens.Contrary to this conventional dichotomy, circulating CD4 ϩ CD8 ϩ T cells have sporadically been reported in humans as well as in animals such as mice, chicken, swine, and monkeys. [1][2][3][4][5][6] The existence of this unconventional and rare (Ͻ 5%) lymphocyte population in the peripheral blood was explained as a premature release of CD4 ϩ CD8 ϩ T cells from the thymus into the periphery, 7,8 where their maturation into functionally competent single-positive cells continues. 7 There is, however, considerable evidence of an increased frequency of peripheral CD4 ϩ CD8 ϩ T cells during viral infections. [9][10][11][12] In human immunodeficiency virus (HIV) or EpsteinBarr virus (EBV) infections, for example, the percentage of CD4 ϩ CD8 ϩ T cells can increase to 20% of all circulating lymphocytes. 9,10 Yet, in humans, very little is known about their phenotype, antigen specificity, and function. This is particularly striking since in animal models CD4 ϩ CD8 ϩ T cells have been described as antigen-specific memory cells that can be induced by vaccination. 3,4,6 Thus, it is crucial to determine the role and biologic significance of peripheral CD4 ϩ CD8 ϩ T cells in humans, as they could potentially contribute to the adaptive immune response against pathogens.In this study, we addressed this issue with an extensive analysis of peripheral CD4 ϩ CD8 ϩ T cells in both healthy individuals and patients with past or present viral infections. We determined the frequency and ex vivo phenotype of CD4 ϩ CD8 ϩ T cells in regards to memory, activation, homing, differentiation, and maturation markers. Furthermore, we provide data on antigen specificity, proliferation, cytokine production, and cytotoxic potential of CD4 ϩ CD8 ϩ T cells in response to tetanus toxoid and to a large variety of antigens (lysates of infected cells, overlapping viral peptides, minimal optimal viral epitopes) from past (influenza A virus [IV] Materials and methods Blood samplesPeripheral blood mononuclear cells (PBMCs) were isolated from anticoagulant citrate dextrose (ACD)-anticoagulated blood of 10 healthy blood donors and 15 HCV-infected patients as described. 13 Viral lysates, peptides, proteins, and antibodiesLysates from CMV-or EBV-infected cells and the corresponding uninfected cells were purchased from Virion (Marristown, NJ). Lysates from HSV-1-, MV-, and VZV-infected cells and the c...
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