The Role of the Adaptive Immune Response During HCV Infection

The adaptive immune response is mediated by lymphocytes expressing antigen-specific receptors, T and B lymphocytes. B lymphocytes secrete immunoglobulins that play a major role in the capture of pathogens by macrophages (opsoni-sation) and in blocking antigenic sites critical for the life cycle of the pathogen.

Seroconversion in HCV occurs approximately 7 to 31 weeks after primary infection (Pawlotsky, 1999, 2004), and some HCV-specific antibodies are effective in blocking in vitro infection of target cells by HCV (Farci et al., 1994). However, in both chimpanzees and humans, naturally acquired anti-HCV antibodies generated during this infection do not seem to be protective upon secondary infection with HCV, indicating that these molecules play a limited role in preventing the spread of the virus (Farci et al., 1992; Lai et al., 1994). Moreover, studies in chimpanzees indicate that resolution of infection can occur without the development of detectable antibody responses (Cooper et al., 1999). In addition, recent studies using HCV pseudotyped particles indicate that neutralizing anti-HCV antibodies occur far more commonly in persistently infected individuals than in those who clear the virus (Bartosch et al., 2003; Logvinoff et al., 2004; Meunier et al., 2005). A recent report has suggested that antibodies might be essential for the control of non-cytopathic viruses and to maintain protective memory (Bachmann et al., 2004). It is therefore possible that antibodies play other unsuspected roles during HCV infections. These roles will certainly be explored in future studies.

Although the recent advent of HCV strains capable of in vitro replication and infectivity (Lindenbach et al., 2005; Wakita et al., 2005) is likely to enhance our understanding of the role of neutralizing antibodies in HCV infection, the role of T cells in viral control is better understood than the role of B cells. Thus, this review will focus on T cell-mediated immunity.

In contrast to immunoglobulins able to recognize soluble antigens, T lymphocytes express a T cell receptor that recognizes a degraded form of the antigen associated with a molecule encoded by the major histocompatibility complex (MHC). This peptide/MHC complex is formed, processed, and presented on the surface of an antigen-presenting cell (APC). Expression of CD4 or CD8 molecules distinguishes two distinct types of T lymphocytes exerting different functions: CD4+ T cells recognize MHC class II molecules, secrete cytokines, and are often referred to as T helper cells, while CD8+ T cells recognize MHC Class I molecules, secrete cytokines with antiviral properties, kill target cells, and are known as cytotoxic T cells (CTL).

Adaptive immune responses mediated by T cells are essential in the control of HCV and viral clearance. In both chimpanzees and humans, viral clearance is associated with sustained CD4+ and CD8+ T cells responses and an increase of IFN-y expression in the liver (Thimme et al., 2002). Recent studies in which memory CD4+ and CD8+ T cells were depleted have confirmed the critical role of these cells in controlling HCV infection (Grakoui et al., 2003; Shoukry et al., 2003).

The chronological evolution of T cell immune responses in HCV infection can be classically divided into three phases (Bowen & Walker, 2005a) (Figure 1): the first phase corresponds to the first weeks following primary infection. Virus titers increase and become very high during this phase irrespective of future viral clearance or persistence. It is likely that CD4+ and CD8+ T cells specific for HCV are activated very early during this phase. However, one of the most remarkable observations that came out of studies investigating the kinetics of HCV infection in both chimpanzees and humans is that these responses are not detected in the blood before 1-3 months after initial infection (Bowen & Walker, 2005a; Cox et al.,

Fig. 1 Schematic representation of the three phases of HCV infection and of possible disease outcomes [modified version of a figure from Bowen & Walker (2005a)]. All HCV infections are characterized by three different phases: pre-acute, acute, and post-acute. The post-acute phase might lead to either viral persistence (a and b) or viral clearance (c). Three categories of infections can be distinguished: (a) infections in which viremia is never controlled, characterized by weak CD4+ and CD8+ T cell responses; (b) infections that seem to be initially controlled but rebound following loss of CD4+ T cells; (c) infections that are resolved and result in the generation of both memory CD4+ and CD8+ T cells

Fig. 1 Schematic representation of the three phases of HCV infection and of possible disease outcomes [modified version of a figure from Bowen & Walker (2005a)]. All HCV infections are characterized by three different phases: pre-acute, acute, and post-acute. The post-acute phase might lead to either viral persistence (a and b) or viral clearance (c). Three categories of infections can be distinguished: (a) infections in which viremia is never controlled, characterized by weak CD4+ and CD8+ T cell responses; (b) infections that seem to be initially controlled but rebound following loss of CD4+ T cells; (c) infections that are resolved and result in the generation of both memory CD4+ and CD8+ T cells

2005a). The median time for the development of a IFN-y response is 33 days (Cox et al., 2005a). The reasons for this delay are not yet understood and will be discussed at the end of this chapter. The second phase of the disease is characterized by acute transient hepatitis that persists for a few weeks. Infected individuals may develop acute hepatitis irrespective of the outcome of infection. A rise in serum levels of alanine aminotransferase (ALT), a marker of hepatocyte damage, is associated with the emergence of detectable CD4+ and CD8+ T cell immune responses and a drop in viral titers. These responses have been shown to peak between 180-360 days after initial infection (Cox et al., 2005a). The last phase depends on the outcome of the disease; in 30% of infected individuals, virus is cleared and infection resolves. In these individuals, ALT levels normalize and CD4+ and CD8+ memory T cells persist. In approximately 70% of HCV infections, infection becomes chronic. This phase is usually characterized by an absent or almost undetectable HCV-specific CD4+ T cell response and a poor or ineffective CD8+ T cell response. In the following two sections we will review the characteristics of CD4 and CD8 T cells responses during acute and chronic HCV.

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