Clonal proliferation of hepatocytes and progression of liver disease in chronic hepatitis B virus infection

慢性乙型肝炎病毒感染中肝细胞的克隆增殖和肝病进展

• 批准号: nhmrc : 453507
• 负责人: A/Pr Allison Jilbert
• 金额: $ 28.04万
• 依托单位: The University of Adelaide
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/clonal-proliferation-hepatocytes-virus-infection/95778
• 关键词: Clonal; proliferation; hepatocytes; progression; liver

Infection with the hepatitis B virus (HBV) can lead to either acute resolving, or chronic HBV infection. Chronic HBV infections are often associated with severe liver disease, and increased risk of liver cancer and occur worldwide in 350 million people. HBV infects hepatocytes, the major cell of the liver. Early during infection 100% of hepatocytes are infected. However, this percentage declines over time to 10-50% or less. The reasons for this are unknown. We suggest that changes in the liver cell population occur because of the immune response against infected hepatocytes. We hypothesize that the immune response kills infected hepatocytes and provides and growth advantage to hepatocytes that can no longer be infected with HBV. This leads to the clonal proliferation of HBV-negative hepatocytes that over time become the major cell population in the liver. We will study human liver tissue using molecular techniques to detect the HBV DNA that integrates randomly into cell DNA during HBV infection. We will then determine the copy number of specific integrated virus-cell junctions as a measure of hepatocyte proliferation. Sections of fixed liver will also be examined for changes in histology and frequency of HBV infection. These studies will determine if foci of HBV-negative hepatocytes are clonal. This finding would suggest that a major role of the immune system in the development of liver cancer is to restrict the genetic pool of hepatocytes. We hypothesise that liver cancer beings with a very specific survival advantage for hepatocytes that lack HBV replication and antigen expression, and that proliferation of these cells expands the pool of potentially altered HCC precursor cells.

感染B型肝炎病毒（HBV）可导致急性缓解或慢性HBV感染。慢性HBV感染通常与严重的肝脏疾病有关，并增加肝癌的风险，全球有3.5亿人发生。HBV感染肝细胞，肝的主要细胞。感染早期100%的肝细胞被感染。然而，随着时间的推移，这一比例下降到10-50%或更低，原因不明。我们认为，肝细胞群的变化是由于对感染肝细胞的免疫反应而发生的。我们假设免疫反应杀死了感染的肝细胞，并为不再被HBV感染的肝细胞提供了生长优势。这导致HBV阴性肝细胞的克隆增殖，随着时间的推移，这些肝细胞成为肝脏中的主要细胞群。我们将利用分子生物学技术研究人类肝脏组织，以检测HBV感染过程中随机整合到细胞DNA中的HBV DNA。然后，我们将确定特定整合病毒-细胞连接的拷贝数作为肝细胞增殖的量度。还将检查固定肝脏切片的组织学变化和HBV感染频率。这些研究将确定HBV阴性肝细胞病灶是否为克隆性。这一发现表明，免疫系统在肝癌发展中的主要作用是限制肝细胞的遗传库。我们假设，肝癌是一个非常具体的生存优势，肝细胞缺乏HBV复制和抗原表达，这些细胞的增殖扩大池的潜在改变HCC前体细胞。