乙型肝炎病毒DNA整合和慢性感染肝细胞肝细胞的克隆扩增

StephenW

Hepatitis B Virus DNA Integration and Clonal Expansion of Hepatocytes in the Chronically Infected Liver
William S Mason  1 , Allison R Jilbert  2 , Samuel Litwin  1
Affiliations
Affiliations

    1
    Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
    2
    Department of Molecular and Biomedical Science, School of Biological Sciences, University of Adelaide, Adelaide, SA 5005, Australia.

    PMID: 33573130 DOI: 10.3390/v13020210

Abstract

Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years or decades, lead to fibrosis and cirrhosis, and play a role in the high incidence of hepatocellular carcinoma (HCC) in HBV carriers. Immune-mediated inflammation appears to cause oxidative DNA damage to hepatocytes, which may also play a major role in hepatocarcinogenesis. An additional DNA damaging feature of chronic infections is random integration of HBV DNA into the chromosomal DNA of hepatocytes. While HBV DNA integration does not have a role in virus replication it may alter gene expression of the host cell. Indeed, most HCCs that arise in HBV carriers contain integrated HBV DNA and, in many, the integrant appears to have played a role in hepatocarcinogenesis. Clonal expansion of hepatocytes, which is a natural feature of liver biology, occurs because the hepatocyte population is self-renewing and therefore loses complexity due to random hepatocyte death and replacement by proliferation of surviving hepatocytes. This process may also represent a risk factor for the development of HCC. Interestingly, during chronic HBV infection, hepatocyte clones detected using integrated HBV DNA as lineage-specific markers, emerge that are larger than those expected to occur by random death and proliferation of hepatocytes. The emergence of these larger hepatocyte clones may reflect a survival advantage that could be explained by an ability to avoid the host immune response. While most of these larger hepatocyte clones are probably not preneoplastic, some may have already acquired preneoplastic changes. Thus, chronic inflammation in the HBV-infected liver may be responsible, at least in part, for both initiation of HCC via oxidative DNA damage and promotion of HCC via stimulation of hepatocyte proliferation through immune-mediated killing and compensatory division.

Keywords: clonal expansion; hepatitis B virus; hepatocellular carcinoma; hepatocyte proliferation; immune-mediated killing; virus DNA integration.

StephenW

乙型肝炎病毒DNA整合和慢性感染肝细胞肝细胞的克隆扩增
威廉·梅森1，艾莉森·吉尔伯特2，塞缪尔·利特温1
隶属关系
隶属关系

    1个
    福克斯·蔡斯癌症中心，费城，宾夕法尼亚州19111，美国。
    2
    阿德莱德大学生物科学学院分子与生物医学科学系，阿德莱德，SA 5005，澳大利亚。

    PMID：33573130 DOI：10.3390 / v13020210

抽象的

人乙型肝炎病毒（HBV）可以引起肝脏的长期终生感染，这可能导致针对病毒感染的肝细胞的持续性或偶发性免疫介导的炎症。这种免疫反应导致病毒感染的肝细胞的杀灭率升高，这可能持续数年或数十年，导致纤维化和肝硬化，并在HBV携带者肝细胞癌（HCC）的高发率中起作用。免疫介导的炎症似乎引起肝细胞氧化DNA损伤，这也可能在肝癌发生中起主要作用。慢性感染的另一种DNA破坏特征是HBV DNA随机整合到肝细胞的染色体DNA中。尽管HBV DNA整合在病毒复制中没有作用，但它可能会改变宿主细胞的基因表达。实际上，在HBV携带者中出现的大多数HCC都含有整合的HBV DNA，而且在许多情况下，整合物似乎在肝癌的发生中起作用。肝细胞的克隆扩增是肝生物学的自然特征，因为肝细胞群体是自我更新的，因此由于随机的肝细胞死亡和被存活的肝细胞增殖替代而失去了复杂性。该过程也可能代表肝癌发生的危险因素。有趣的是，在慢性HBV感染期间，使用整合的HBV DNA作为谱系特异性标记物检测到的肝细胞克隆的出现，比预期的因肝细胞随机死亡和增殖而出现的克隆要大。这些较大的肝细胞克隆的出现可能反映了生存优势，这可以通过避免宿主免疫反应的能力来解释。虽然这些较大的肝细胞克隆大多数可能不是肿瘤前性肿瘤，但有些可能已经获得肿瘤前性变化。因此，HBV感染的肝脏中的慢性炎症可能至少部分负责通过氧化DNA损伤引发HCC和通过免疫介导的杀伤和代偿性分裂刺激肝细胞增殖来促进HCC。

关键词：克隆扩增乙型肝炎病毒;肝细胞癌；肝细胞增殖；免疫介导的杀伤病毒DNA整合。

StephenW

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