The Outcome of Hepatitis C Virus Infection Is Predicted by Escape Mutations in Epitopes Targeted by Cytotoxic T Lymphocytes

Erickson, Ann L.; Kimura, Yasumi; Igarashi, Suzu; Eichelberger, Jennifer S.; Houghton, Michael; Sidney, John; McKinney, Denise M.; Sette, Alessandro; Hughes, Austin L.; Walker, Christopher M.

doi:10.1016/s1074-7613(01)00245-x

Cited by 375 publications

(356 citation statements)

References 32 publications

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“…This phenomenon may represent an additional pivotal mechanism establishing HCV persistence [45,46]. However, in this study the question remains unresolved why CTL specific for unrelated viruses (i.e.…”

Section: Discussionmentioning

confidence: 90%

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: the role of the virus

Accapezzato¹,

Francavilla²,

Rawson³

et al. 2004

Eur J Immunol

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In a companion study, we showed a dichotomy between the expansion of central memory (CCR7 + ) hepatitis C virus (HCV)-specific CTL and the incomplete memory effector differentiation in patients with acute HCV infection. Indeed, effector cells were unable to perform immediate functions, despite expressing the tissue-homing phenotype of effector memory cells (CCR7 -; semi-effectors). However, since they promptly differentiated into full-effectors upon IL-2 contact, we suggested that the inhibitory effect by environmental (possibly viral) factors on IL-2 production may have a pivotal role in generating the large population of semieffector CCR7 -/IFN-+ -CTL. In accord with this view, we report here strong evidence in support of circulating HCV core protein (HCVcore) playing a central role in inhibiting effector CTL differentiation, but not memory CTL expansion. The regulatory HCVcore effect is related to inhibition of the signal transduction pathway instrumental for IL-2 production, supporting the evidence that IL-2 was capable both of pushing semi-effector CTL to complete their effector cell program and of restoring the HCVcore-dependent inhibitory effect. Therefore, the strength of CTL activation is dependent on the balance between the threshold of stimulatory signals and the viral interference capacities provided during priming.

show abstract

Section: Discussionmentioning

confidence: 90%

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: the role of the virus

Accapezzato¹,

Francavilla²,

Rawson³

et al. 2004

Eur J Immunol

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show abstract

“…However, the finding that patients resolving infection showed a broader effector CTL repertoire indicates that the multispecificity could compensate the defect of CTL responses, and ultimately control the establishment of chronic infections [38][39][40][41]. Further data are clearly needed to elucidate this complex issue, principally in order to analyze the possible signals influencing the generation of multispecific CTL responses in some HCVinfected individuals.…”

Section: Discussionmentioning

confidence: 99%

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms

et al. 2004

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Hallmark of acute hepatitis C virus (HCV) infection is a severe virus-specific effector CD8 + T cell dysfunction that seems to be a critical factor in preventing the resolution of infection and in favoring the onset of chronic liver immunopathology. We suggest that this dysfunction is critical in the establishment of HCV persistence, unless it is compensated by multispecific responses, as found in individuals resolving infection. Analyses on purified populations indicate that central memory HCV-specific CCR7 + /CD8 + T cells efficiently proliferate and differentiate in vitro, although the large population of memory effector CCR7 -cells found in the peripheral blood of acutely infected patients display poor effector functions ex vivo (semieffectors). However, we report strong evidence in support of IL-2 being capable of pushing semi-effector CTL to complete their effector cell program. Therefore, IL-2 deficiency during T cell activation may be responsible for the dichotomy between memory CTL expansion and incomplete effector differentiation shown in patients with acute HCV infection. These data are consistent with the possible therapeutic treatment with IL-2 to rebuild the effector T cell pool in these patients.

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“…These characteristics of HCV contribute to the marked genomic diversity of HCV, with the potential to induce viral variants that can evade immune recognition [143; 144]. Erickson et al first demonstrated immune escape from CD8+ T cell in the chimpanzee model [145]. Mutation occurred within multiple MHC class I restricted epitopes but not flanking regions of the HCV genome within the first few months of chronic infection.…”

Section: Sequence Mutationsmentioning

confidence: 99%

Immune responses during acute and chronic infection with hepatitis C virus

Ishii

Koziel

2008

Clinical Immunology

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Hepatitis C virus (HCV) induces persistent infection and causes chronic liver disease in most infected patients. Vigorous HCV-specific CD4+ and CD8+ T cell responses against HCV multiple epitopes are necessary for spontaneous viral clearance during the acute phase, but the virus appears to have multiple strategies to evade these defenses. There are relatively few studies on the role of immune responses during the chronic phase of infection. CD4+ T cell responses appear to protect against liver injury and may be important to clearance during interferon and ribavirin based therapy. Classic cytotoxic T cells (CTL) may primarily damage the liver in chronic HCV, but there may be subpopulations of T cells that protect against liver inflammation. Resolution of these outstanding questions is important to the development of a prophylactic vaccine as well as improving therapeutic options for those with chronic infection.

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The Outcome of Hepatitis C Virus Infection Is Predicted by Escape Mutations in Epitopes Targeted by Cytotoxic T Lymphocytes

Cited by 375 publications

References 32 publications

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: the role of the virus

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: the role of the virus

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms

Immune responses during acute and chronic infection with hepatitis C virus

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The Outcome of Hepatitis C Virus Infection Is Predicted by Escape Mutations in Epitopes Targeted by Cytotoxic T Lymphocytes

Cited by 375 publications

References 32 publications

Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: the role of the virus

Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: the role of the virus

Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms

Immune responses during acute and chronic infection with hepatitis C virus

Contact Info

Product

Resources

About

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: the role of the virus

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: the role of the virus

Subversion of effector CD8⁺ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms