Mutational Escape from Cellular Immunity

The relationship between cell-mediated immunity and the outcome of HCV infection has been established by numerous studies. Memory CD8+ cytotoxic T cells (CTL) are required for protection against persistent HCV infection; at the same time, durable intrahepatic memory is likely established during acute HCV infection, since T cells recognizing HCV antigens have been recovered from the livers of chimpanzees several years after spontaneous clearance of infection (Shoukry et al. 2004). Consequently, the outcome of HCV infection may be dictated by escape mutations in the epitopes targeted by CTL (Erickson et al. 2001). On this issue, one report demonstrated that CTL escape mutations occurred in persistent HCV infection (Cox et al. 2005). A second report described that divergent and convergent virus evolution after a common-source outbreak of HCV affected disease outcome (Ray et al. 2005). Immune evasion leading to persistent infection, in contrast to recovery from viral infection, after acute HCV infection from a shared source has been reported (Tester et al. 2005), reinforcing the general relevance of this immune evasion mechanism to persistence of RNA viruses in humans (Bowen and Walker 2005a). Amino acid changes also can alter

Fig. 10 Possible mechanisms of immune evasion by HCV infection or viral protein expression. All possible steps of immune dysfunction caused by HCV infection are italicized

CTL recognition of variant peptide-MHC complexes (Bowen and Walker 2005b). This and other mechanisms of HCV persistence are outlined in Fig. 10.

Successful immune responses in HCV infection generally target multiple major MHC class I-restricted epitopes in structural and nonstructural HCV proteins (Cooper et al. 1999; Shoukry et al. 2004). At the earliest time point studied in persons infected with HCV, highly activated CTL populations were observed that temporarily failed to secrete interferon (IFN)-y, a "stunned" phenotype, from which they recovered as viremia declined (Lechner et al. 2000). In long-term HCV-seropositive persons, CTL responses were more common in those who had cleared viremia than those with persistent viremia, although the frequencies of HCV-specific CTL were lower than what was found in persons during and after resolution of acute HCV infection (Lechner et al. 2000).

CTL escape mutants are found during HCV infection in humans (Chang et al. 1997). Escape mutations in MHC class I-restricted epitopes are a feature of HCV infection that can diminish CTL responses via several mechanisms. For mutations in the CTL epitopes, marked fitness cost is not exacted by viral escape, and reversion to a more immunogenic ancestral state is not automatic upon passage to a host in which immune selection pressure is absent. It is tempting to speculate that this phenomenon might be due to low fitness cost associated with this particular mutation, thus allowing persistence of the variant sequence in the absence of immune selection pressure. A loss of epitope phenotype can also occur when amino acid anchor residues required for MHC binding are changed (Chang et al. 1997;

Erickson et al. 2001). Evidence for the emergence of escape mutations and their role in HCV infection are well-documented. The evolution of escape mutations in HCV is likely constrained by both intrinsic viral factors and certain characteristics of the adaptive immune response (see Sect. 2 above). There are several supporting reports on the lack of protective immunity against reinfection with HCV (Lai et al.

1994), the failure of naturally acquired antibodies to prevent reinfection of immune chimpanzees or humans (Farci et al. 1992), and emergence of CTL escape variants (Weiner et al. 1995).

Immune selection of HCV variants in humans includes the following steps (Bowen and Walker 2005a). First, mutations occur in immune epitopes of both structural and nonstructural viral proteins during acute infection. Second, evolution of quasispecies occurs in early infection. Third, a divergent or convergent CTL mutational evolutionary pattern from the prototypical epitope has been observed following a common-source HCV outbreak (Bowen and Walker 2005b; Ray et al. 2005; Tester et al. 2005). Some of these mutations are due to viral reversion to a more fit ancestral state (Cox et al. 2005; Ray et al. 2005). Nonetheless, these adaptive mutations can temper the effectiveness of CD8+ CTL function (Franzin et al.

1995). There is a complex interplay between the breadth and specificity of the antigen-specific immune response and the degree to which mutations selected by this immune pressure govern viral reproduction. Fourth, limited epitope variation occurs during the late or chronic infection phase. Last, epitope variation can be present (restricting MHC allele vs nonrestricting MHC) without seroconversion during chronic infection (Post et al. 2004). Similarly in chimpanzees, immune selection of HCV variants includes the following observations (Cooper et al. 1999; Bowen and Walker 2005b). First, there is a minimal viral variation prior to onset of adaptive immune response. Second, escape mutations abrogating CTL function do occur in acute phase infection. Third, escape mutations evading the antiviral CTL response occurs in MHC class I-restricted epitopes (Weiner et al. 1995; Sasso 2000; Erickson et al. 2001).

Immune escape by mutations in CTL epitopes occurs by at least two mechanisms (Drummer et al. 2002; Bowen and Walker 2005a, b), the loss of T cell receptor (TCR) recognition (Ivanovski et al. 1998; De Re et al. 2000; Sasso 2000; inhibition of CTL response, antigenic sin, and preferential stimulation of response) and the loss of epitope by altered proteasome processing and reduced MHC class I binding. The amino acid substitutions within or adjacent to CTL epitopes can alter proteasomal processing, causing epitope destruction before transport to the endo-plasmic reticulum for MHC binding (Seifert et al. 2004; Timm et al. 2004; Kimura et al. 2005). In HLA-A*01- and B*08-negative individuals, absence of these alleles was associated with evolution toward consensus within epitopes restricted by these MHC molecules (Ray et al. 2005).

The viral epitopes on the virus-specific CD4+ and CD8+ T cell frequently evolve during HCV infection, resulting in impaired effector function of HCV-specific CTL (Gruener et al. 2001; Wedemeyer et al. 2002) and a lack of protective immunity against reinfection with HCV (Lai et al. 1994). In the presence of the restricting allele, mutational escape of MHC class I-restricted epitopes may occur in four ways. First, sustained cellular immune responses are associated with resolution of infection during the acute phase (Zuckerman et al. 1997). The diverse clonal CTL TCR repertoire due to sustained CD4+ T cell response may constrain the development of escape mutations in the restricting MHC molecule. Second, in the case of absent or weak CD4+ T cell responses, CTL responses are weak and CTL-escape mutations may not develop (Hanley et al. 1996; De Vita et al. 2000). Third, where the CD4+ T cell response fails, escape mutations might emerge, particularly if their fitness cost is low. Lastly, if the TCR repertoire of the clonal CTL is narrow in the absent or weak CD4+ T cell response, escape mutations may emerge (Grakoui et al. 2003; Shoukry et al. 2004). In the absence of the restricting allele, when there is low associated fitness cost or well-developed compensatory mutations and if there is no CTL-mediated immune pressure, the mutated sequence may persist or may mutate to an equally "fit" alternative. Where there is high fitness cost associated with the presence of an escape mutation and if there is no CTL-mediated immune pressure (minimal immune selection pressure), reversion to the wild-type ("fitter") sequence is likely to occur.

Epitope mutations in individual MHC alleles may alter the interaction of epitope with the immune system by at least four different mechanisms. First, mutational escape from CD8+ T cell immunity can occur (Bowen and Walker 2005a, b). Second, mutations in cognate epitopes in anchoring residues may lead to dissociation of the MHC-peptide complex. Third, mutations in the epitope or in flanking regions can alter proteasomal processing, leading to destruction of the epitope. Fourth, reduced TCR recognition of the neo-epitope-MHC complex is involved (Chang et al. 1997). TCR recognition may be reduced or possibly altered, leading to antagonism against responses to the wild-type peptide. Such mutated peptide-MHC complexes may alternatively antagonize responses to the wild-type epitope (Chang et al. 1997; Kaneko et al. 1997; Tsai et al. 1998). Nonsynonymous mutations may occur within CTL epitopes or within regions flanking these sequences.

Other immunological mechanisms (Bowen and Walker 2005b, c) are MHC class II-restricted escape mutations (Misiani et al. 1994), CD4+ T cell response from Th1 toward Th2 response (Casato et al. 2002), marked CD4+ CD25+ regulatory T cells (Rushbrook et al. 2005), regulatory CD8+ T cell, MHC class I-restricted antigen-specific regulatory activity with the potential to suppress antiviral T cells (Koziel et al. 1995), narrow CD8+ T cell receptor repertoire and impaired dendritic cell maturation in chronic hepatitis C patients (Auffermann-Gretzinger et al. 2001). Memory CD8+ T cells can vary in differentiation phenotype in different persistent virus infections (Appay et al. 2002). HCV persistence and immune evasion do occur in the absence of memory T cell help (Grakoui et al. 2003). A role of primary intrahepatic T cell activation in the "liver tolerance effect" has been reported (Bertolino et al. 2002). Finally, the upregulation of inhibitory receptor programmed death-1 (PD-1) expression has been shown to lead to HCV-specific CD8 exhaustion (Tseng and Klimpel 2002). Thus, due likely to interplay between the opposing forces of immune selection pressure and viral fitness cost, a variety of outcomes are possible upon initial infection with HCV, or after subsequent transmission of the virus to a recipient in whom the initial MHC class I alleles are not expressed.

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