CAM-A-dependent HBV core aggregation induces apoptosis through ANXA1.

Area of Science:

• Hepatology and Virology
• Molecular Biology
• Drug Discovery

Background:

• Chronic Hepatitis B virus (HBV) infection is a leading cause of liver disease and hepatocellular carcinoma, with limited effective antiviral therapies.
• Capsid assembly modulators (CAMs) inhibit HBV replication by targeting the HBV core antigen (HBc), but their precise mechanisms in HBV-hepatocyte interactions are not fully understood.

Purpose of the Study:

• To investigate the mechanism of cell death induced by CAM-A compounds in Hepatitis B virus (HBV) infection.
• To elucidate the role of HBV core protein (HBc) aggregation and apoptosis in CAM-A's antiviral activity.

Main Methods:

• Utilized an HBV infection model, HBc-overexpressing cells, primary human hepatocytes, and HBV-replicating cells (HepAD38).
• Assessed HBsAg reduction, cell toxicity, HBc aggregation, and apoptosis.
• Performed transcriptomic analysis to identify molecular pathways involved.
• Investigated the role of ANXA1 by gene silencing.

Main Results:

• CAM-A treatment reduced HBsAg levels and induced cell toxicity in HBV-infected cells.
• CAM-A treatment caused nuclear aggregation of HBc, leading to apoptosis.
• Transcriptomic analysis revealed ANXA1 upregulation, a known apoptosis driver.
• Silencing ANXA1 expression delayed CAM-A-induced cell death and apoptosis.

Conclusions:

• CAM-A compounds induce cell death through ANXA1-driven apoptosis, triggered by nuclear HBc aggregation.
• This mechanism provides a novel therapeutic strategy for eliminating HBV-infected cells.
• The findings open new avenues for achieving a functional cure for chronic HBV infection.