Hepadnavirus Infections and Liver Cancer

嗜肝DNA病毒感染和肝癌

• 批准号: 6965836
• 负责人: William Mason
• 金额: $ 46.15万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965836
• 关键词: Hepadnaviridae; antiviral agents; drug resistance; gene expression; hepatocellular carcinoma; host neoplasm interaction; liver cells; marmots; microorganism disease chemotherapy; neoplasm /cancer genetics; preneoplastic state; tissue /cell culture; viral carcinogenesis; virus genetics; virus infection mechanism; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): The host immune response to chronic HBV infection produces persistent liver injury leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), in parallel with partial clearance of the virus from a large fraction of hepatocytes. However, antiviral therapies to completely eliminate the infection are ineffective in 70-90% of carriers. In contrast, transient infections can be rapidly cleared through the action of the immune system in over 90% of adults newly infected with HBV. Ideally, rational approaches for treatment should be via manipulation of the immune system to induce a similar rapid clearance of chronic infections, or the application of antiviral drug therapies that mimic key steps in the antiviral response. However, there is little agreement about the essential components of viral clearance during a transient infection, and almost nothing is known about the basis for partial clearance in chronic infections. The following specific aims will address these issues, using woodchucks transiently and chronically infected with woodchuck hepatitis virus. Specific Aim 1: A major unresolved issue is whether massive cell death is essential during resolution of hepadnavirus infections in order to eliminate viral nucleic acids from the liver. Experiments will be carried out to determine how viral nucleic acids are eliminated from hepatocytes and whether hepatocyte death and compensatory proliferation may play an essential role in this process. Specific Aim 2: We recently obtained evidence of clonal expansion (>1000 cells/clone) of a large fraction of hepatocytes in livers of chronically infected woodchucks, and hypothesize that partial clearance of the virus as well as neoplastic progression may be byproducts of clonal selection of hepatocytes that have lost the ability to support high titer WHV replication. We will test this hypothesis and examine the possibility that this selection might also be used therapeutically to repopulate the liver with virus resistant hepatocytes. In summary, these studies will determine if cell death and compensatory regeneration are essential for virus clearance by the immune system. They will also determine if experimental induction of an antiviral state in a subpopulation of hepatocytes has therapeutic value or, in contrast, may enhance progression to HCC by facilitating outgrowth of virus resistant hepatocytes with oncogenic mutations.

描述（由申请方提供）：宿主对慢性HBV感染的免疫应答产生持续性肝损伤，导致纤维化、肝硬化和肝细胞癌（HCC），同时从大部分肝细胞中部分清除病毒。 然而，完全消除感染的抗病毒治疗对70-90%的携带者无效。 相比之下，在超过90%的新感染HBV的成年人中，短暂感染可以通过免疫系统的作用迅速清除。 理想情况下，合理的治疗方法应该是通过操纵免疫系统来诱导慢性感染的类似快速清除，或者应用模拟抗病毒反应中关键步骤的抗病毒药物治疗。 然而，在短暂感染过程中，对病毒清除的基本组成部分几乎没有一致意见，对慢性感染中部分清除的基础几乎一无所知。 以下具体目标将解决这些问题，使用土拨鼠短暂和慢性感染土拨鼠肝炎病毒。 具体目标1：一个尚未解决的主要问题是，在嗜肝DNA病毒感染的解决过程中，大量细胞死亡是否是必要的，以便从肝脏中消除病毒核酸。将进行实验以确定病毒核酸如何从肝细胞中消除，以及肝细胞死亡和代偿性增殖是否在此过程中发挥重要作用。 具体目标二：我们最近获得了慢性感染土拨鼠肝脏中大部分肝细胞克隆扩增（>1000个细胞/克隆）的证据，并假设病毒的部分清除以及肿瘤进展可能是肝细胞克隆选择的副产品，这些肝细胞已经失去了支持高滴度WHV复制的能力。 我们将测试这一假设，并检查这种选择也可能用于治疗的可能性，以病毒抗性肝细胞重建肝脏。 总之，这些研究将确定细胞死亡和代偿性再生是否是免疫系统清除病毒所必需的。他们还将确定在肝细胞亚群中实验诱导抗病毒状态是否具有治疗价值，或者相反，是否可以通过促进具有致癌突变的病毒抗性肝细胞的生长来促进HCC的进展。