Review
T cell response in hepatitis C virus infection

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Abstract

Hepatitis C virus (HCV) is a hepatotropic RNA virus that causes acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. It is widely accepted that cellular immune responses play an important role in viral clearance and disease pathogenesis. However, HCV often evades effective immune recognition and has a propensity to persist in the majority of acutely infected individuals (ca. 80%). The immunological and virological basis for the inefficiency of the cellular immune response to clear or control the virus is not known. Recent studies, however, have provided new insights into the mechanisms of viral clearance and persistence that will be discussed in detail.

Introduction

With an estimated 200 million people infected world-wide, hepatitis C virus (HCV) infection represents a major healthcare challenge. HCV is a single-stranded ribonucleic acid (RNA) virus that belongs to the Flaviviridae family. Man is the only natural host of HCV, though experimental infection of chimpanzees is possible. Only about 20% of acutely HCV-infected patients present with clinical symptoms, e.g., fatigue, fever, abdominal pain, or jaundice (Orland et al., 2001). Interestingly, about 50% of symptomatic patients eliminate the virus whereas an asymptomatic course of acute HCV infection results in chronic HCV infection in about 80% (Gerlach et al., 2003). In some HCV-infected patients, chronic hepatitis leads to liver fibrosis, cirrhosis and ultimately hepatocellular carcinoma (HCC). The host immune responses against HCV play an important role in both, viral control as well as disease pathogenesis and will be discussed below.

Section snippets

Host immune response to HCV

Host immune responses consist of various components (Parkin and Cohen, 2001): innate immunity comprises physical barriers (e.g., skin and mucous membranes), cellular components (e.g., granulocytes, macrophages and natural killer (NK) cells), and soluble components (e.g., complement factors and type I interferons [IFN-α, IFN-β]). Adoptive immunity is composed of humoral immunity (e.g., antibodies produced by B cells) and, most important in viral infections, cellular immunity (e.g., CD4+ and CD8+

Successful T cell response to acute HCV infection

Initial studies of acutely HCV-infected patients revealed that a strong, multispecific and sustained HCV-specific CD4+ T cell response is associated with a self-limited course of infection (Diepolder et al., 1995, Gerlach et al., 1999, Missale et al., 1996). CD4+ T cell responses are directed mainly against non-structural proteins of HCV and often target the same immunodominant epitopes within the non-structural protein NS3 (Diepolder et al., 1997, Hoffmann et al., 1995).

More recent studies of

Failure of the T cell response to HCV infection

As described above and shown in Fig. 1, there is growing consensus that vigorous and multispecific HCV-specific CD4+ and CD8+ T cell responses are required for viral clearance and protective immunity. However, viral clearance occurs only in a minority of cases, whereas about 80% of acutely HCV-infected individuals develop chronic infection. Various mechanisms of T cell failure leading to viral persistence have been suggested (Table 1), but so far most of them are poorly defined. In the

HCV-specific immune responses in the liver

The liver appears to be an organ that favors the induction of immune tolerance rather than immunity (Limmer et al., 2000). Indeed, hepatocytes as well as other cells of the liver, such as liver sinusoidial endothelial cells (LSECs) may play an important role in generating tolerance. Little information is currently available, however, about the role of the liver and its specific environment in establishing viral persistence in HCV infection.

Importantly, HCV-specific CD4+ and CD8+ T cell

Concluding remarks

Studies during the last few years have led to a better understanding of the viral and immunological factors that determinate viral clearance, viral persistence, disease activity and progression in HCV infection. Viral clearance and liver disease are mediated by a vigorous T cell response in the liver with cytotoxic and non-cytotoxic effector functions (Fig. 1). The virus persists, however, in the majority of acutely infected patients. The mechanisms that lead to the failure of the HCV-specific

Acknowledgements

The authors thank Dr. Hans Christian Spangenberg for critically reading the manuscript. The work described in this review was supported by grants R01-CA76403 and R01-AI20001 from the National Institutes of Health (USA) and by a grant from the Deutsche Forschungsgemeinschaft (Th719 2-1, Emmy Noether Programm) and a fellowship from the Cancer Research Institute to R.T. Currently, R.T. is supported by grants from the Deutsche Forschungsgemeinschaft (Th719 2-2, Emmy Noether Programm), HepNet, and

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    1

    This author received the Heine-Medin Award 2003 from the European Society of Clinical Virology.

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