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

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.

Oncogenic viral antigens for engineered T cell immunotherapy: Challenges and opportunities

“…One of the patients experienced a partial recovery that lasted for 27.7 months. Importantly, following HBV-TCR-T cell infusion, the majority of the patients showed a decrease in circulating HBsAg and HBV DNA levels or their stability, demonstrating on-target effects [18]. In another phase I clinical trial (NCT04677088), autologous T cells that expressed specific TCRs encoded by the incorporation of HBV-DNA into the host DNA were introduced.…”

“…When HBsAg‐CART cells were adoptively transferred into HBV‐infected humanized mice, the levels of HBsAg and HBV‐DNA in the liver significantly dropped in comparison with those in control animals. Notably, after treatment with HBsAg‐specific CAR‐T cells, the proportion of HBV core–positive hepatocytes among all human hepatocytes significantly decreased, suggesting noncytopathic viral elimination [18].…”

“…Notably, after treatment with HBsAg-specific CAR-T cells, the proportion of HBV core-positive hepatocytes among all human hepatocytes significantly decreased, suggesting noncytopathic viral elimination [18].…”

Effect analysis of peg-interferon on chronic hepatitis B virus infection

“…Although it is di cult for patients with high baseline HBsAg to achieve clinical cure, the decrease of HBsAg is helpful to reduce the occurrence of liver cirrhosis and liver cancer to a certain extent. A retrospective study conducted in Taiwan, China, showed that patients treated with peginterferon had a lower incidence of hepatocellular carcinoma (HCC) than those treated with nucleoside (acid) analogues (P = 0.011) [14].Studies have shown that long-term exposure to HBsAg in the circulation can lead to an imbalance of immune response, thus forming an immune tolerance microenvironment, and thus promoting tumor progression [15].…”

Novel diagnostic, therapeutic, and prognostic biomarkers for nonalcoholic steatohepatitis-derived hepatocellular carcinoma: Capable to overcome the heterogeneity-specific barrier

“…Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity worldwide (Shah, et al 2022, Sung, et al 2021). Multiple studies have shown that the main risk factors for HCC are chronic hepatitis B and C virus infections, alcohol abuse, and obesity (Ghosh, et al 2021, Iannacone and Guidotti 2022, Konyn, et al 2021, Nabih 2020, Villanueva 2019). The disease burden is signi cantly higher when a combination of HCC and nonalcoholic fatty liver disease (NAFLD) is seen, a common occurrence due to the current obesity epidemic (Ahmad, et al 2022, Villanueva 2019).…”