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Review
. 2021 Aug 30:12:678537.
doi: 10.3389/fmicb.2021.678537. eCollection 2021.

Persistence of Hepatitis B Virus Infection: A Multi-Faceted Player for Hepatocarcinogenesis

Suchandrima Ghosh  1 , Anannya Chakraborty  1 , Soma Banerjee  1
Affiliations
Review

Persistence of Hepatitis B Virus Infection: A Multi-Faceted Player for Hepatocarcinogenesis

Suchandrima Ghosh et al. Front Microbiol. .

Abstract

Hepatitis B virus (HBV) infection has a multi-dimensional effect on the host, which not only alters the dynamics of immune response but also persists in the hepatocytes to predispose oncogenic factors. The virus exists in multiple forms of which the nuclear localized covalently closed circular DNA (cccDNA) is the most stable and the primary reason for viral persistence even after clearance of surface antigen and viral DNA. The second reason is the existence of pregenomic RNA (pgRNA) containing virion particles. On the other hand, the integration of the viral genome in the host chromosome also leads to persistent production of viral proteins along with the chromosomal instabilities. The interferon treatment or administration of nucleot(s)ide analogs leads to reduction in the viral DNA load, but the pgRNA and surface antigen clearance are a slow process and complete loss of serological HBsAg is rare. The prolonged exposure of immune cells to the viral antigens, particularly HBs antigen, in the blood circulation results in T-cell exhaustion, which disrupts immune clearance of the virus and virus-infected cells. In addition, it predisposes immune-tolerant microenvironment, which facilitates the tumor progression. Thus cccDNA, pgRNA, and HBsAg along with the viral DNA could be the therapeutic targets in the early disease stages that may improve the quality of life of chronic hepatitis B patients by impeding the progression of the disease toward hepatocellular carcinoma.

Keywords: HBV; HBV persistence; HCC; hepatitis B Virus; hepatocellular carcinoma.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic diagram representing (A) HBV infection and disease progression, (B) HBV DNA and ALT level in different disease phases, and (C) HBV genome as 3.2 kb relaxed circular DNA (rcDNA) with 5′-covalently bound HBV polymerase possessing direct repeat 1 (DR1) and direct repeat 2 (DR2) along with 2 enhancers ENI and ENII. The HBV genome transcribes to generate different sets of RNAs: pregenomic RNA (3.5 kb) and subgenomic RNAs like PreS1/S (2.4 kb), PreS2/S (2.1 kb), and HBX (0.7 kb). The RNAs contain overlapping (denoted by dotted red lines) and frame-shifted ORFs (depicted by the AUG start codon) for each of the viral proteins. The dotted box indicates the most variable region and mutation hotspot of HBV.
FIGURE 2
FIGURE 2
Schematic representation of the causal factors for HBV persistence leading to predisposed oncogenic effect on liver along with the direct oncogenic effect of the viral genome and proteins on hepatocarcinogenesis.
See this image and copyright information in PMC

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