HBx-induced HSPB1 is a potential therapeutic target owing to its modulation of HBV cccDNA and hepatic immune responses

Background & Aims

Chronic infection with hepatitis B virus (HBV) remains a significant public health concern, and current therapies are inadequate. Here, we report that HBx-elevated heat shock protein B1 (HSPB1) contributes to the regulation of HBV covalently closed circular DNA (cccDNA) and the hepatic immune responses.

Methods

Molecular and cellular in vitro assays were employed to investigate the effects and underlying mechanisms of HSPB1 on HBV cccDNA and HBV replication in HBV-infected cells. The anti-viral efficacy of candidate agents targeting cccDNA and the immune response was assessed in HBV-infected cells, human-liver chimeric mice, and hydrodynamic injection-based HBV-persistent immunocompetent C57BL/6 mice.

Results

HSPB1 enhanced cccDNA stability by reducing the recruitment and binding of APOBEC3A/APOBEC3B to cccDNA. Interaction with HBx led to increased cellular levels of HSPB1 by decreasing its ubiquitination, and nuclear accumulation of HSPB1 was promoted via its enhanced phosphorylation. Therapeutically, we developed a peptide, D-TK, derived from HBXIP peptide sequence that targets HBx and limits cccDNA by blocking the interaction between HSPB1 and HBx, ultimately resulting in reduced HBV replication. Nobly, D-TK reduced the frequency of regulatory T (Treg) cells and enhanced the frequency and activity of CD8⁺ T cells through HSPB1, thereby contributing to suppression of HBV replication.

Conclusions

HSPB1 represents a novel therapeutic target by modulating HBV cccDNA and immune responses in the liver. D-TK is a promising clinical candidate for HBV treatment through cccDNA suppression and immune activation.

Impact and Implications

Chronic infection with HBV remains a significant global health concern, and current therapeutic options are inadequate. In this study, we demonstrate that HBx-induced elevation of HSPB1 contributes to the regulation of HBV cccDNA and the hepatic immune responses. We engineered a peptide, D-TK, that targets HBx, effectively suppresses cccDNA, and activates immune responses through HSPB1. Our findings offer new insights into the mechanism by which HBx-induced HSPB1 modulates HBV cccDNA and immune regulation in the liver.