SARS-CoV-2 spike protein enhances HBV replication via autophagy and aggravates inflammation in CHB patients with liver dysfunction

ABSTRACT This study investigated the effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S protein) on hepatitis B virus (HBV) replication and immune function in patients with chronic hepatitis B (CHB), aiming to elucidate the underlying mechanisms of S protein–HBV interaction. Through in vitro cell experiments and clinical sample analyses, S protein expression was induced in HepG2.2.15 cells, leading to enhanced HBV replication; this effect was reduced by autophagy inhibitors, confirming the critical mediating role of autophagy. Furthermore, peripheral blood mononuclear cells (PBMCs) from CHB patients were co-cultured with the S protein, resulting in increased inflammatory responses in T cells and monocytes, particularly in patients with concurrent abnormal liver function and lipid metabolism disorders. In summary, the S protein promotes HBV replication by activating autophagy and exacerbates immune inflammation in CHB patients. Autophagy inhibitors block its effect on HBV replication, suggesting autophagy as a key regulatory target. The immune-activating effects of the S protein are more pronounced in patients with liver dysfunction and metabolic abnormalities. These findings provide a basis for further investigation into the interplay between the S protein and autophagy in HBV infection. IMPORTANCE This study reveals that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein promotes hepatitis B virus (HBV) replication by activating the autophagy pathway and elucidates its role in exacerbating immune inflammation in patients with chronic hepatitis B, particularly showing more pronounced responses in patients with liver dysfunction and lipid metabolism disorders. These findings provide critical molecular insights into the viral interaction and immunopathological mechanisms during SARS-CoV-2 and HBV co-infection. They also improve our understanding of the interplay between SARS-CoV-2 and HBV in the context of co-infection and provide a basis for future studies.