Gastroenterology
Volume 132, Issue 2 , Pages 801-805, February 2007

T and B Cells in Hepatitis C Virus Control: What They Do and When They Fail

  • Carlo Ferrari

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Carlo Ferrari, MD, Unità Operativa di Malattie Infettive ed Epatologia, Azienda Ospedaliero-Universitaria di Parma, Via A. Gramsci 14, 43100 Parma, Italy. fax: (39) 0521 703857.

Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

published online 03 February 2007.

Article Outline

 

See “Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C” by Kaplan DE, Sugimoto K, Newton K, Valiga ME, Ikeda F, Aytaman A, Nunes FA, Lucey MR, Vance BA, Vonderheide RH, Reddy KR, McKeating JA, and Chang K-M on page 654 and “Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo” by von Hahn T, Yoon JC, Alter H, Rice CM, Rehermann B, Balfe P, and McKeating JA on page 667.

A high rate of chronic persistence is the hallmark of hepatitis C viral (HCV) infection. Indeed, 50%–80% of patients with HCV infection develop chronic hepatitis, with possible evolution to cirrhosis and hepatocellular carcinoma. The type of immune response that the infected host is able to mount early following infection is believed to dictate strongly the outcome toward control or persistence of HCV. However, longitudinal studies of innate and adaptive immune responses from the early stages of HCV infection are limited because most infections are asymptomatic. Therefore, additional studies are needed to clarify the immune events associated with HCV clearance or persistence.

Early Control of HCV Infection: The Innate Immune Response. As in other virus infections, a rapid and efficient activation of the different components of the innate immune system is crucial not only for the initial containment of virus replication and spread, but also for a timely and efficient promotion of downstream adaptive responses, which require more time for their induction but are essential for complete and persistent control of infection.1 HCV seems to be able to induce efficiently type I interferon (IFN) response genes and seems to be sensitive in vitro to IFNs.1 However, a number of in vitro studies suggests that HCV may have developed strategies to modulate the antiviral function of the innate immunity by blocking intracellular signaling pathways to attenuate the IFN antiviral effect,2 and by interfering with natural killer (NK) cell activation and dendritic cell maturation.1 If the results of all these in vitro studies can be actually applied to the pathogenesis of natural HCV infection, 2 important consequences may arise. First, innate responses may only partially and insufficiently contribute to the initial containment of HCV spread, and second, innate responses may inadequately promote and support the physiologic priming of adaptive HCV-specific responses.

Early Kinetics of HCV-Specific Adaptive Responses. Although information about the early kinetics of the T-cell response in natural HCV infection is limited, available data indicate that despite the rapid onset of HCV replication, HCV-specific T-cell responses are induced after an unexpectedly long interval of time from exposure, compared with other viral infections.1, 3, 4 These delayed responses appear also to be functionally impaired at variable degrees based on different studies. The breadth and intensity of CD4-mediated responses have been unanimously reported to be greater in patients with a self-limited infection compared with patients unable to control infection spontaneously,5, 6, 7, 8, 9, 10 who generally mount weaker and more narrowly focused responses. Impaired responses were described initially by proliferation assays with recombinant proteins that measure the capacity of T-cell expansion on long-term culture in vitro, but similar results have more recently been reported by ex vivo analysis of the T-cell response, which more accurately reflects the in vivo immune reactivity of the infected host. By ex vivo intracellular cytokine staining, CD4-mediated responses at the time of the ALT peak appear to be predominantly Th1 oriented, with a production of IFN-γ and interleukin (IL)-2 efficient in patients who succeed in clearing HCV spontaneously, but deeply impaired in patients with a chronically evolving acute infection.7 This impairment of the CD4-mediated response is not necessarily expression of a primary failure of the CD4 reactivity in persisting infections, because early HCV-specific CD4 responses that subsequently waned have been reported in some acute patients who became chronically infected.3, 10 Moreover, in this issue of Gastroenterology, Kaplan et al11 extend this concept, reporting a hierarchical impairment of the CD4 reactivity in acute HCV infection. Although successful virus control was associated with both efficient proliferation and robust IFN-γ production by CD4 cells, in some patients with chronic evolution of infection, isolated proliferation or IFN-γ production were detected transiently but subsequently waned at later follow-ups. Thus, all available studies of the early acute stages of HCV infection are concordant in concluding that HCV-specific CD4 cells are dysfunctional in chronically evolving acute infections and that these early functional inactivation can deeply affect antiviral protection.

By contrast, a variable degree of functional impairment has been reported for HCV-specific CD8 responses in the acute stage of HCV infection. By tetramer staining ex vivo, CD8 cells specific for preselected and widely recognized epitopes can generally be detected in the circulation of infected patients some weeks after infection.3, 7, 8, 12, 13 Despite visibility by tetramers, HCV-specific CD8 cells can be dysfunctional because they can be unable for some additional weeks after their induction to produce IFN-γ and IL-2 on ex vivo peptide stimulation.3, 4, 7, 8, 13 This early CD8 dysfunction is generally detectable regardless of the subsequent outcome to virus control or persistence. Moreover, it is not a general feature of the overall HCV-specific CD8 cell population, because IFN-γ production can be detected by intracellular cytokine staining and ELISPOT analysis ex vivo when the T-cell response is analyzed with comprehensive panels of peptides covering the whole HCV sequence, which can give a more global representation of the antiviral CD8 response.7, 8, 13 By these experimental approaches, CD8 responses in the acute phase of infection appear to be directed simultaneously against multiple HCV sequences,7, 8, 13 but they do not significantly differ in self-limited and evolving infection with respect to breath and vigor,7, 8, 9, 10, 11, 12, 13 as confirmed by Kaplan et al.11 These CD8 populations of different epitope specificity may be widely heterogeneous with respect to function, with coexistence in individual patients of functionally impaired and functionally preserved HCV-specific CD8 cells.14 In summary, human studies are consistent with the interpretation that functionally efficient CD4 responses are determinant in dictating the fate of infection by directly contributing to virus control. The impact of CD8 cells on HCV pathogenesis is less clear. Although depletion studies in the chimpanzee model are consistent with a role for CD8 cells as primary effector of protective immunity,4 studies in natural HCV infection were unable to find clear correlations between HCV-specific CD8 responsiveness and outcome of infection.

In this scenario, the role of the neutralizing antibody response in HCV pathogenesis is still largely undefined, because studies of the humoral response have until recently been hampered by the lack of simple in vitro models to evaluate antibody-dependent neutralization of HCV infection. This limitation has recently been overcome by 2 major breakthroughs: the identification of the JFH strain of HCV, which can replicate in cell culture with release of infectious particles,15, 16, 17 and the generation of infectious retrovirus-HCV pseudoparticles produced by assembling HCV envelope glycoproteins on a retroviral core.18, 19 By using the latter tool, broadly reactive neutralizing antibodies have been detected at high titers in patients with a long-lasting condition of chronic HCV infection.19 The pseudoparticle model has been applied by Kaplan et al11 to compare neutralizing antibody responses in patients with resolving and chronically evolving acute hepatitis C. Detection of neutralizing antibodies, which were broadly cross-reactive across genotypes, did not correlate with viral clearance; thus, neutralizing antibodies are certainly generated in the HCV-infected host, but they do not seem to represent the main driving force of HCV control. An important piece of information to understand why HCV can coexist with neutralizing antibodies escaping their antiviral effect is provided by the report of von Hahn et al20 in this issue of Gastroenterology.

Mechanisms of Failure of Adaptive Responses in HCV Infection. HCV is a RNA virus with a high propensity to mutate because of the lack of proofreading capacity of its polymerase. This property gives HCV the potential capacity to escape T- and B-cell surveillance by mutating residues relevant to T- and B-cell recognition of immunodominant epitopes. The availability of longitudinal serum and peripheral blood mononuclear cell samples from a chronic HCV patient with a very well-defined source of infection prompted von Hahn et al20 to generate a series of HCV pseudoparticles expressing patient-derived HCV glycoproteins from sequential time points following infection to assess the neutralizing effect of autologous and heterologous serum samples and to seek direct evidence of escape. Antibody responses constantly failed to neutralize autologous HCV glycoprotein sequences detectable in the serum at the same or later time points, and good neutralizing activity was generally observed against earlier viral sequences. Sequential emergence of viral mutations able to abrogate B-cell recognition of the viral envelope glycoprotein sequence was demonstrated, consistent with a model of virus escape from B-cell surveillance, where antibodies present at a given time point in the infected host can neutralize earlier viral strains but are ineffective against the concurrent virus. This can explain why high titers of neutralizing antibodies are present in chronic patients but are unable to control the coexisting viral strains.

Identification of mutations in CD4 and CD8 epitopes, located within the HCV envelope antigens,20 which can completely abrogate T-cell recognition of the preexisting epitopes, supports the possibility that not only CD8 but also CD4 cells can exert a selective pressure able to cause the emergence of escape variants. How CD4 cells can actually exert a direct immunologic pressure able to select mutated epitopes remains, however, to be elucidated. By contrast, mutational escape from CD8 responses has previously been convincingly demonstrated in acute patients with persistent HCV infection,7, 14, 21, 22, 23, 24 suggesting a possible role for this mechanism in the pathogenesis of HCV chronicity. However, its relevance as a primary determinant of HCV persistence remains an open question if activation of CD8 responses is actually delayed after infection and the strength of the selection pressure exerted by CD8 cells is actually weakened by the suppressive effect of early inhibitory mechanisms. These include (1) T-cell exhaustion owing to the rapid viral spread in the infected host causing an early exposure of T cells to high virus and antigen loads25; (2) the intrinsic properties of the different HCV proteins, which can modulate the antiviral T-cell response, either by suppressing the T-cell function directly or by interfering with NK and dendritic cell activity, making these cells unable to adequately support priming and activation of virus-specific adaptive responses1; and (3) a hyperactivity of suppressive CD4+CD25+FoxP3-positive cells.9, 26

Data published in this issue of Gastroenterology extend results of previous studies supporting the view that HCV is likely able to acquire an early survival advantage over the host immune system thanks to its fast replication kinetics and its capacity to interfere with the early intracellular pathways of antiviral defense. These intrinsic features of the virus may also impact on priming and maturation of adaptive responses through T-cell exhaustion, mutational escape from T- and B-cell surveillance, and negative modulation of the early cross-talk between innate and adaptive immunity, providing the virus with an additional survival advantage that can contribute to the high rate of HCV persistence (Fig. 1).

  • View full-size image.
  • Figure 1. 

    HCV can outpace the immune response. The intrinsic replication kinetics of HCV and the intrinsic inhibitory properties of the HCV proteins can provide HCV with an initial survival advantage over the immune system. These early mechanisms can set in motion a series of sequential events that together provide HCV with a high likelihood to evade immune surveillance and to persist. DC, dendritic cell; CTL, cytotoxic T lymphocyte; Th1 and Th2, T helper 1 and T helper 2.

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References 

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PII: S0016-5085(07)00012-1

doi:10.1053/j.gastro.2007.01.010

Refers to article:

  • Hepatitis C Virus Continuously Escapes From Neutralizing Antibody and T-Cell Responses During Chronic Infection In Vivo , 06 December 2006

    Thomas von Hahn, Joo Chun Yoon, Harvey Alter, Charles M. Rice, Barbara Rehermann, Peter Balfe, Jane A. McKeating
    Gastroenterology February 2007 (Vol. 132, Issue 2, Pages 667-678)

  • Discordant Role of CD4 T-Cell Response Relative to Neutralizing Antibody and CD8 T-Cell Responses in Acute Hepatitis C , 06 December 2006

    David E. Kaplan, Kazushi Sugimoto, Kimberly Newton, Mary E. Valiga, Fusao Ikeda, Ayse Aytaman, Frederick A. Nunes, Michael R. Lucey, Barbara A. Vance, Robert H. Vonderheide, K. Rajender Reddy, Jane A. McKeating, Kyong–Mi Chang
    Gastroenterology February 2007 (Vol. 132, Issue 2, Pages 654-666)

Gastroenterology
Volume 132, Issue 2 , Pages 801-805, February 2007

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