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: 11.19). 07/2006; 44(1):126-39. DOI: 10.1002/hep.21242
Source: PubMed

ABSTRACT 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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    • "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 · 10.40 Impact Factor
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    • "Typically, patients with self-limited acute HCV infection undergo sustained viral clearance within the first 12 weeks of disease onset, whereas viremia beyond 6 months generally indicates chronic evolution (4). The divergent outcomes of acute HCV infection are known to be determined by differences in virus-specific T-cell responses among patients (5–9). "
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    ABSTRACT: Hepatitis C virus (HCV) infects approximately 170 million people worldwide and is a major cause of life-threatening liver diseases such as liver cirrhosis and hepatocellular carcinoma. Acute HCV infection often progresses to chronic persistent infection, although some patients recover spontaneously. The divergent outcomes of acute HCV infection are known to be determined by differences in virus-specific T-cell responses among patients. Of the two major T-cell subsets, CD8(+) T-cells are known to be the key effector cells that control viral infections via cytolytic activity and cytokine secretion. Herein, we review various aspects of HCV-specific CD8(+) T-cell responses in acute HCV infection. In particular, we focus on timing of CD8(+) T-cell responses, relationship between CD8(+) T-cell responses and outcomes of acute HCV infection, receptor expression on CD8(+) T-cells, breadth of CD8(+) T-cell responses, and viral mutations.
    Frontiers in Immunology 06/2014; 5:266. DOI:10.3389/fimmu.2014.00266
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    • "However, due to the very low frequency of circulating HBV- and HCV-specific CD4+ T cells, very little is known about the exact differentiation and function of these cells. Taken together, HBV- and HCV-specific CD4+ T cells do not seem to primarily mediate direct antiviral effects, but play an important role for the clearance of the virus by enhancing the effector responses of virus-specific CD8+ T cells.23,40,41 "
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    ABSTRACT: Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are global health problems affecting 600 million people worldwide. Indeed, HBV and HCV are hepatotropic viruses that can cause acute and chronic liver disease progressing to liver cirrhosis and even hepatocellular carcinoma. Furthermore, co-infections of HBV and HCV with HIV are emerging worldwide. These co-infections are even more likely to develop persistent infection and are difficult to treat. There is growing evidence that virus-specific CD4+ and CD8+ T-cell responses play a central role in the outcome and pathogenesis of HBV and HCV infection. While virus-specific T-cell responses are able to successfully clear the virus in a subpopulation of patients, failure of these T-cell responses is associated with the development of viral persistence. In this review article, we will discuss similarities and differences in HBV- and HCV-specific T-cell responses that are central in determining viral clearance, persistence and liver disease.
    Emerging Microbes and Infections 03/2013; 2(3). DOI:10.1038/emi.2013.14
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