Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses

Laboratory of Viral Immunopathology, Department of Infectious Diseases and Hepatology, Azienda Ospedaliera di Parma, Parma, Italy.
Hepatology (Impact Factor: 11.06). 07/2006; 44(1):126-39. DOI: 10.1002/hep.21242
Source: PubMed


A timely, efficient, and coordinated activation of both CD4 and CD8 T cell subsets following HCV infection is believed to be essential for HCV control. However, to what extent a failure of the individual T cell subsets can contribute to the high propensity of HCV to persist is still largely undefined. To address this issue, we analyzed the breadth, vigor, and quality of CD4 and CD8 responses simultaneously with panels of peptides covering the entire HCV sequence or containing the HLA-A2-binding motif, and with recombinant HCV proteins in 16 patients with acute HCV infection by tetramer staining, ELISPOT, and intracellular cytokine staining for interferon gamma, interleukin (IL)-2, IL-4, and IL-10. Our results indicate that at clinical onset, CD8 responses are similarly weak and narrowly focused in both self-limited and chronically evolving infections. At this stage, CD4 responses are deeply impaired in patients with a chronic outcome as they are weak and of narrow specificity, unlike the strong, broad and T helper 1-oriented CD4 responses associated with resolving infections. Only patients able to finally control infection show maturation of CD8 memory sustained by progressive expansion of CD127+ CD8 cells. Thus, a poor CD8 response in the acute stage of infection may enhance the overall probability of chronic viral persistence. In conclusion, the presence of functional CD4 responses represents one of the factors dictating the fate of infection by directly contributing to control of the virus and by promoting maturation of protective memory CD8 responses.

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    • "Furthermore, an increase in peripheral HCV-specific T cell IFNc response was noted by the end of treatment. Contrary, impaired HCV-specific responses were more pronounced in HIV/HCV coinfected patients without subsequent restoration during PegIFNa/RBV therapy [41] [42] [43] [44] [45]. In addition, it was shown that intra-hepatic T cells were less capable of IFNc production in an ELIspot assay [46]. "
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    ABSTRACT: Evidence over the past decades have shown that HIV/HCV coinfected patients did not respond as well to HCV therapy as HCV mono-infected patients. However, these paradigms are being recently reassessed with the improvements of care for HIV and HCV patients. This article reviews these original paradigms and how the new data is impacting upon them. Treatment efficacy now appears comparable for HIV/HCV coinfected and HCV mono-infected patients, while liver fibrosis progression is increasingly similar in optimally managed patients. Additional importance of therapy is directed to drug-drug interactions and the impact of HCV reinfection, as well as the possibility of transmitted drug resistance.
    Journal of Hepatology 08/2015; 345(5). DOI:10.1016/j.jhep.2015.06.034 · 11.34 Impact Factor
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    • "Despite the plethora of studies on CD8 T cells, it is still not entirely clear what kind of CD8 T cell response is required to achieve full control of HCV. Again, as with CD4 responses, vigorous and broadly directed CD8 responses were observed in self-limited disease [17] [28], but if individuals were studied within the initial 6 months of HCV infection, similarly strong CD8 responses could be seen in patients with a chronic course of infection [22]. What we understand better, compared to the CD4 responses, are the different mechanisms that render the HCV-specific CD8 T cell response debilitated and unable to control the virus throughout the progression to persistent viraemia. "
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    ABSTRACT: Hepatitis C virus (HCV) infects an estimated more than 150 million people and is a leading cause of liver disease worldwide. The development of direct-acting antivirals (DAAs) will markedly improve the outcome of antiviral treatment with cure of the majority of treated patients. However, several hurdles remain before HCV infection can be considered a menace of the past: High treatment costs will most likely result in absent or limited access in middle and low resource countries and will lead to selective use even in wealthier countries. The limited efficacy of current HCV screening programs leads to a majority of cases being undiagnosed or diagnosed at a late stage and DAAs will not cure virus-induced end-stage liver disease such as hepatocellular carcinoma. Certain patient subgroups may not respond or not be eligible for DAA-based treatment strategies. Finally, reinfection remains possible, making control of HCV infection in people with ongoing infection risk difficult. The unmet medical needs justify continued efforts to develop an effective vaccine, protecting from chronic HCV infection as a mean to impact the epidemic on a global scale. Recent progress in the understanding of virus–host interactions provides new perspectives for vaccine development, but many critical questions remain unanswered. In this review, we focus on what is known about the immune correlates of HCV control, highlight key mechanisms of viral evasion that pose challenges for vaccine development and suggest areas of further investigation that could enable a rational approach to vaccine design. Within this context we also discuss insights from recent HCV vaccination studies and what they suggest about the best way to go forward.
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.09.009 · 11.34 Impact Factor
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    • "result from impairment at different levels of this regulatory network during its adjustment. Loss of HCV-specific CD4 T cell responses and IL-2 production as consistently observed in patients developing chronic infection is one mechanism that could interfere with proper induction of T-bet in CD8 T cells (Diepolder et al., 1995; Gerlach et al., 1999; Urbani et al., 2006). Furthermore, several studies have reported that HCV core protein disturbs APC maturation during acute HCV infection , leading to decreased levels of IL-12, which could contribute to loss of interferon- production (Auffermann-Gretzinger et al., 2001; Eisen-Vandervelde et al., 2004). "
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    ABSTRACT: The transcription factor T-bet regulates the production of interferon-γ and cytotoxic molecules in effector CD8 T cells, and its expression correlates with improved control of chronic viral infections. However, the role of T-bet in infections with differential outcome remains poorly defined. Here, we report that high expression of T-bet in virus-specific CD8 T cells during acute hepatitis B virus (HBV) and hepatitis C virus (HCV) infection was associated with spontaneous resolution, whereas T-bet deficiency was more characteristic of chronic evolving infection. T-bet strongly correlated with interferon-γ production and proliferation of virus-specific CD8 T cells, and its induction by antigen and IL-2 stimulation partially restored functionality in previously dysfunctional T-bet-deficient CD8 T cells. However, restoration of a strong interferon-γ response required additional stimulation with IL-12, which selectively induced the phosphorylation of STAT4 in T-bet(+) CD8 T cells. The observation that T-bet expression rendered CD8 T cells responsive to IL-12 suggests a stepwise mechanism of T cell activation in which T-bet facilitates the recruitment of additional transcription factors in the presence of key cytokines. These findings support a critical role of T-bet for viral clearance and suggest T-bet deficiency as an important mechanism behind chronic infection.
    Journal of Experimental Medicine 09/2014; 211(10). DOI:10.1084/jem.20131333 · 12.52 Impact Factor
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