Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses
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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ABSTRACT: Hantaviruses infection causing severe emerging diseases with high mortality rates in humans has become public health concern globally. The potential roles of CD4+T cells in viral control have been extensively studied. However, the contribution of CD4+T cells to the host response against Hantaan virus (HTNV) infection remains unclear. Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4+T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome. A total of 79 novel 15-mer T-cell epitopes on the HTNV glycoprotein were identified, among which 20 peptides were dominant target epitopes. Importantly, we showed the presence of both effective Th1 responses with polyfunctional cytokine secretion and ThGranzyme B+ cell responses with cytotoxic mediators production against HTNV infection. The HTNV glycoprotein-specific CD4+T-cell responses inversely correlated with the plasma HTNV RNA load in patients. Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4+T-cell responses against HTNV glycoproteins compared with more severe patients. The CD4+T cells characterized by broader antigenic repertoire, stronger polyfunctional responses, better expansion capacity and highly differentiated effector memory phenotype(CD27-CD28-CCR7-CD45RA-CD127hi) would elicit greater defense against HTNV infection and lead to much milder outcome of the disease. The host defense mediated by CD4+T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells. Thus, these findings highlight the efforts of CD4+T-cell immunity to HTNV control and provide crucial information to better understand the immune defense against HTNV infection.PLoS Pathogens 04/2015; 11(4):e1004788. DOI:10.1371/journal.ppat.1004788 · 8.06 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) infection is an important public health problem worldwide. HCV exploits complex molecular mechanisms, which result in a high degree of intrahost genetic heterogeneity. This high degree of variability represents a challenge for the accurate establishment of genetic relatedness between cases and complicates the identification of sources of infection. Tracking HCV infections is crucial for the elucidation of routes of transmission in a variety of settings. Therefore, implementation of HCV advanced molecular surveillance (AMS) is essential for disease control. Accounting for virulence is also important for HCV AMS and both viral and host factors contribute to the disease outcome. Therefore, HCV AMS requires the incorporation of host factors as an integral component of the algorithms used to monitor disease occurrence. Importantly, implementation of comprehensive global databases and data mining are also needed for the proper study of the mechanisms responsible for HCV transmission. Here, we review molecular aspects associated with HCV transmission, as well as the most recent technological advances used for virus and host characterization. Additionally, the cornerstone discoveries that have defined the pathway for viral characterization are presented and the importance of implementing advanced HCV molecular surveillance is highlighted.Viruses 03/2015; 7(3):1153-1188. DOI:10.3390/v7031153 · 3.28 Impact Factor