Bim-mediated attrition of virus-specific CD8 T cells in chronic HBV infection

乙型肝炎病毒仍然是当今世界十大杀手之一，每年造成约100万人死于慢性肝病，导致肝功能衰竭和肝癌。有一种疫苗可以防止传播，但这对估计已经受到慢性感染的4亿人来说毫无用处。现在有许多药物可用于治疗乙型肝炎感染，但这些药物通常只能抑制病毒，而不是清除病毒；当病人停止治疗时，病毒水平又会回升。这里提出的工作目标是让我们开发一种治疗补充来增强免疫控制，这样昂贵且有潜在毒性的抗病毒药物只需要在短时间内使用。我们将通过平行实验来解决这个问题，同时使用小鼠模型和直接从患者身上研究的细胞，包括那些针对乙型肝炎病毒感染的最新治疗方法。我们已经在T细胞（一种关键类型的杀伤免疫细胞）中发现了一个关键缺陷，这可能是它们在慢性感染患者中无法控制乙型肝炎病毒的原因。我们发现，当它们遇到乙型肝炎病毒时，它们的T细胞会被触发自杀；存活下来的细胞太少，无法控制感染。这项提议的目的是找出是什么导致了这种细胞自杀，以及是否可以安全地阻止它以允许T细胞的恢复。然后，这可能会使免疫反应恢复到成功的类型，即在不需要药物治疗的情况下，设法自然控制这种感染。

Hepatitis B virus remains one of the top ten killers in the world today, causing around a million deaths every year from chronic liver disease, leading to liver failure and liver cancer. There is a vaccine to prevent spread, but this is of no use to the 400 million people estimated to already be chronically infected. There are now a number of drugs available to treat hepatitis B infection but these typically only suppress the virus rather than clear it; when the patient stops the treatment the virus level comes back up. The goal of the work proposed here is to allow us to develop a type of treatment supplement to boost immune control, such that costly and potentially toxic antiviral drugs would only need to be given for a short period. We will address this by parallel experiments using both a mouse model and also cells studied directly from patients, including those on the latest treatments available for hepatitis B virus infection. We have identified a critical defect in T cells (a key type of killer immune cell), which could account for their failure to control hepatitis B virus in patients with chronic infection. We have found that their T cells are triggered to commit suicide when they encounter hepatitis B virus; too few of these cells then survive to control the infection. This proposal aims to work out what drives this cell suicide and whether it can be safely blocked to allow a recovery of T cells. This could then switch the immune response back to the successful type seen in people who manage to control this infection naturally without requiring drug treatment.