Redirecting T cells to overcome tolerance 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。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。目前尚无有效的药物治疗肝衰竭和肝癌的终末期并发症。这里提出的工作目标是使我们能够开发一种治疗方法，以安全增强对乙型肝炎病毒感染的免疫控制。我们希望利用免疫系统中T细胞的自然能力来控制这种病毒。在慢性乙型肝炎病毒感染的患者中，正确类型的T细胞很少，所以我们将对患者进行基因工程改造？T细胞重新获得对抗乙型肝炎病毒的能力。这项提议旨在通过在试管和小鼠模型中模拟这种情况，研究这些基因工程T细胞在抵抗肝脏中的乙型肝炎病毒方面的效果。我们的研究结果将为这种方法在肝炎和其他慢性感染和肿瘤中的应用提供必要的信息。

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. 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. There is no effective drug therapy for the end-stage complications of liver failure and liver cancer.The goal of the work proposed here is to allow us to develop a type of treatment to safely boost immune control of hepatitis B virus infection. We would like to harness the natural ability of a component of the immune system called T cells to control this virus. There are very few of the right type of T cells left in patients with chronic hepatitis B virus infection, so we will genetically engineer the patients? T cells to regain the ability to fight against hepatitis B virus. This proposal aims to look into how effective these genetically engineered T cells will be at combatting hepatitis B virus when it is in the liver, by mimicking this situation in a test tube and in a mouse model. Our findings will provide essential information for the future application of this approach to hepatitis and other chronic infections and tumours.