Sustained Dysfunction of Antiviral CD8⁺T Lymphocytes after Infection with Hepatitis C Virus

Abstract

Hepatitis C virus (HCV) sets up persistent infection in the majority of those exposed. It is likely that, as with other persistent viral infections, the efficacy of T-lymphocyte responses influences long-term outcome. However, little is known about the functional capacity of HCV-specific T-lymphocyte responses induced after acute infection. We investigated this by using major histocompatibility complex class I-peptide tetrameric complexes (tetramers), which allow direct detection of specific CD8؉ T lymphocytes ex vivo, independently of function. Here we show that, early after infection, virus-specific CD8؉ T lymphocytes detected with a panel of four such tetramers are abnormal in terms of their synthesis of antiviral cytokines and lytic activity. Furthermore, this phenotype is commonly maintained long term, since large sustained populations of HCV-specific CD8 ؉ T lymphocytes were identified, which consistently had very poor antiviral cytokine responses as measured in vitro. Overall, HCV-specific CD8 ؉ T lymphocytes show reduced synthesis of tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥) after stimulation with either mitogens or peptides, compared to responses to Epstein-Barr virus and/or cytomegalovirus. This behavior of antiviral CD8 ؉ T lymphocytes induced after HCV infection may contribute to viral persistence through failure to effectively suppress viral replication.

Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection

“…Treg might be an important target in future therapies against cancer or chronic infectious diseases [24]. A functional impairment of CD8 + T cells has also been described in chronic viral infection effecting humans, like human immunodeficiency virus (HIV) and hepatitis C virus (HCV) [35][36][37][38][39][40][41]. In addition, in both HIV and HCV infection CD4 + Treg have been reported to suppress antiviral T cell responses [1,[42][43][44][45].…”

Antigen amount dictates CD8+T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

“…During highly replicative chronic viral infections such as HIV-1, hepatitis B or hepatitis C virus infection in humans, or lymphocytic choriomeningitis virus (LCMV) in mice, virus-specific CD8 + T cells initially expand and acquire effector functions early after infection but then gradually lose these functions [1][2][3][4][5][6][7][8] in a hierCorrespondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch archical manner: first the ability to produce IL-2 and to proliferate, then TNF-α secretion and last IFN-γ production become impaired [9][10][11][12]. This T-cell dysfunction, also termed CD8 + T-cell exhaustion, is well studied after infection of mice with a high dose of LCMV clone 13 or LCMV-Docile [13].…”

Increased natural cytotoxicity receptor expression and relevant IL‐10 production in NK cells from chronically infected viremic HCV patients

“…Spontaneous resolution of HCV infection has been linked to vigorous and multi-specific T cell responses, while attenuated CD4 + and CD8 + T cell responses have been observed during the chronic phase of viral persistence [3][4][5][6]. Failure to control HCV replication has also been associated with functional defects of virus-specific CD8 + cytotoxic T lymphocytes (CTL) [7][8][9][10] and, most recently, to the appearance of viral escape mutations in immunodominant CD8 + CTL epitopes associated with a lack of or relative defects in HCV-specific CD4 + T cell responses [11][12][13]. Adaptive immune defects during HCV infection are not limited to HCV-specific immune responses and may reflect the broader effects of HCV on the editing of T cell responses also on other antigen specificities [14].…”