Hepatitis B Virus DNA Integration and Clonal Expansion of Hepatocytes in the Chronically Infected Liver

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.

Targeted long-read sequencing reveals clonally expanded HBV-associated chromosomal translocations in patients with chronic hepatitis B

“…For this reason, it is believed that a large amount of HBsAg in the liver is expressed from integrated HBV DNA. Over time, some hepatocytes harboring HBV integrations may be subject to clonal expansions [18,19]. In particular, HCC samples demonstrate high clonality for integrations, often associated with integrations located in or near oncogenes [3].…”

Current Perspectives on B Lymphocytes in the Immunobiology of Hepatocellular Carcinoma

“…As the main cell-related part in the TME, the distributing process, frequency, and prognosis-related importance exhibited by invasive B cell subsets within HCC is still controversial. Virus-related hepatitis and the occurrence of HCC show an inseparable relationship ( 63 ). An early report stated that the hepatitis C virus (HCV) can infect liver cells by binding to B cells in peripheral blood, increasing the risk of HCC ( 64 ).…”

Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure

“…These effects drive reduction in the reservoir of normal hepatic function, fueling biochemical flare and decompensation. However, the liver has well-established regenerative properties [ 98 , 99 , 100 , 101 ] and clonal expansion of normal hepatocytes has been characterized throughout HBV infection [ 102 , 103 ], although the extent and rate of this clonal expansion has yet to be determined [ 12 ]. Thus, the available reservoir of normal liver function during the progression of HBV is governed by the balance of the loss of normally functioning hepatocytes due to HBV infection and the clearance of HBV infected hepatocytes with the restoration of normally functioning hepatocytes due to regeneration ( Figure 3 ).…”

“…Unfortunately, HBV infection remains chronic in more than 292 million people worldwide [ 7 ] and is responsible for 870,000 deaths annually [ 8 ]. This chronic infection results from (1) the inhibition of the immune response to HBV via the maintenance of abundant circulating HBsAg by the production of a large excess of non-infectious subviral particles (SVP) over virions [ 9 ], (2) the ability of the HBV genome to form a closed covalent circular DNA (cccDNA) “minichromosome” that can reside inside the nucleus of infected cells in an inactive “latent” state [ 10 ] and (3) the integration of HBV DNA into the chromosomes of liver cells [ 11 , 12 ], which progresses with continued chronic infection, becoming a significant source of SVP [ 9 , 13 , 14 , 15 ].…”