Determinants of T-Cell mediated control in acute HCV Infection

最近的研究令人鼓舞，丙型肝炎病毒感染的病毒控制是可能的。 迫切需要预防性疫苗或有效的免疫疗法，以减少 这种全球性的流行病。据估计，全世界有1.7亿人感染HCV，并导致显著的发病率 在发达国家和发展中国家。 各种研究报告了CD4+和CD8+在控制HCV复制中的重要作用。 然而，保护性T细胞免疫的相关性和导致T细胞衰竭的机制， 人类HCV感染还没有很好的了解。显然，结果是在早期阶段确定的。 因此，研究为清除奠定基础的最早事件与 病毒的持久性。.我们建议在这里分析的CD8和CD4 T细胞免疫在大的队列 急性HCV感染和不同传播途径的受试者。我们的核心假设是 HCV感染通常激发CD4和CD8 T细胞应答，但在感染早期， T细胞应答质量的变化要么导致病毒控制，要么在大多数受试者中， 病毒为了验证这一假设，我们建议定义HCV特异性CD8 T细胞的功能概况， 急性HCV感染时抑制性分子组合的表达和激活 感染我们将使用HCV特异性T细胞在功能障碍的不同阶段的转录谱 以及与不同的T细胞抑制分子相关的基因表达特征， 定义导致T细胞应答失败的复杂事件。我们还将确定CD8 T细胞的作用 表达NK标志物CDI61作为初步数据表明，这种人群在病毒感染中的作用， 持久性。除了定义导致CD8 T细胞功能障碍和衰竭的机制外，我们还将 我们还研究了HCV特异性CD4+ T细胞，它们对病毒控制同样重要，如果不是更重要的话，但 被调查得不那么详细。我们最近发现，我们可以识别HCV特异性CD4 T细胞， 在几乎所有急性HCV感染的受试者中， 在我们的大型急性HCV感染受试者队列中直接离体。分析了 免疫介导的控制和T细胞衰竭将是指导发展的重要贡献。 预防性疫苗或免疫疗法。

Recent studies have been encouraging that viral control of hepatitis C virus infection is possible. Prophylactic vaccines or efficient immunotherapies are urgently needed to reduce the disease burden of this global epidemic. HCV infects estimated 170 million people woridwide, and causes significant morbidity in developed and developing countries. Various studies report an important role for both CD4+ and CD8+ in the control of HCV replication. However, the correlates of protective T-cell immunity and the mechanisms causal for T-cell failure in human HCV infection are not well understood.Cleariy, the outcome is determined in the eariy phase of the disease, therefore it seems paramount to study the eariiest events that set the stage for clearance versus persistence of the virus. . We propose here the analysis of CD8 and CD4 T-cell immunity in large cohorts of subjects with acute HCV infection and different transmission routes. Our central hypothesis is that acute HCV infection typically elicits both CD4 and CD8 T cell responses, but that eariy during infection critical changes in the quality of the T-cell response either lead to viral control or, in most subjects, persistence of the virus. To test this hypothesis we propose to define the functional profile of HCV-specific CD8 T-cells in the context of expression and activafion of a combination of inhibitory molecules during acute HCV infection. We will use transcriptional profiles of HCV-specific T-cells during different stages of dysfunction together with gene expression signatures associated with distinct T-cell inhibitory molecules in order to define the complex events leading to a failed T-cell response. We will also determine the role of CD8 Tcells expressing the NK marker CDI61 as preliminary data suggest a role for this populafion in viral persistence. In addifion to defining mechanisms leading to CD8 T-cell dysfunction and exhaustion, we will also invesfigate HCV-specific CD4+ T-cells that are equally, if not more, crifical for viral control but have been investigated in much less detail. We have recently shown that we can identify HCV-specific CD4 Tcells in almost all subjects with acute HCV infection and have developed reagents to analyze these cells directly ex-vivo in our large cohorts of subjects with acute HCV infection. Dissection of the mechanisms of immune mediated control and T-cell failure will be an important contribufion to guide the development of prophylactic vaccines or immunotherapies.