The Outcome of Acute Hepatitis C Predicted by the Evolution of the Viral Quasispecies

Farci, Patrizia; Shimoda, Akihiro; Coiana, Alessandra; Diaz, Giacomo; Peddis, Giovanna; Melpolder, Jacqueline C.; Strazzera, Antonello; Chien, David; Muñoz, Santiago J.; Balestrieri, A; Purcell, Robert H.; Alter, Harvey J.

doi:10.1126/science.288.5464.339

Cited by 804 publications

(669 citation statements)

References 40 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: 91%

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: 91%

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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“…The level of ALT may be 500-2000 IU/l, compared with HBV where it may be 5 or 10 times higher [8][9][10].…”

Section: Clinical Featuresmentioning

confidence: 99%

Cellular immune responses against hepatitis C virus: the evidence base 2002

Ward¹,

Lauer

Isba³

et al. 2002

Clinical and Experimental Immunology

136

101

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SUMMARYHepatitis C virus (HCV) is an RNA virus which is estimated to persistently infect about 170 million people worldwide. After acute infection, there is an initial period during which long-term outcome is decided. There is strong evidence that the cellular immune responses, involving both CD4 + and CD8 + T lymphocytes, are involved at this stage and it is their effectiveness which determines outcome. What is not understood is what determines their effectiveness. The most important component of this is likely to be some aspect of epitope selection, itself dictated by host MHC. Thus, to understand host immunity to HCV, we need to have a detailed understanding of the peptides involved in T lymphocyte responses. In this review, we discuss the peptide epitopes that have been identified so far, and their potential significance. We relate this to a scheme of host defence which may be useful for understanding natural and vaccine-induced immunity.

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The Outcome of Acute Hepatitis C Predicted by the Evolution of the Viral Quasispecies

Cited by 804 publications

References 40 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

Cellular immune responses against hepatitis C virus: the evidence base 2002

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The Outcome of Acute Hepatitis C Predicted by the Evolution of the Viral Quasispecies

Cited by 804 publications

References 40 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

Cellular immune responses against hepatitis C virus: the evidence base 2002

Contact Info

Product

Resources

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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