The sV184A Variant in HBsAg Specific to HBV Subgenotype C2 Leads to Enhanced Viral Replication and Apoptotic Cell Death Induced by PERK‐eIF2α‐CHOP‐Mediated ER Stress

HBV genotype C, particularly subgenotype C2, is associated with an elevated risk of HCC and aggressive disease activity. We previously identified a nonsynonymous sV184A variant in the HBsAg region, predominantly in HBV subgenotype C2. This study investigates the mechanistic role of the sV184A variant in promoting liver disease progression. Analysis of 109 chronically HBV-infected patients revealed that the sV184A variant correlates with significantly elevated HBV DNA. Both patient data and public database indicated that sV184A is associated with high frequency of BCP mutations, however, the high HBV DNA in the sV184A group are independent of the presence of BCP mutations. In vitro and in vivo studies demonstrated that the sV184A variant enhances HBV replication and induces ER stress via the PERK-eIF2α-CHOP pathway, leading to apoptosis. HBV large surface (LHB)(LHB) protein was found to be a key factor, responsible for the strong ER stress, as the sV184A variant increases LHB protein stability. Pharmacological inhibition of PERK signaling or mutation of the LHB mitigated HBV proliferation and apoptosis induced by the sV184A variant. The sV184A variant specific to HBV subgenotype C2 significantly promotes HBV replication and apoptosis, serving as a driver of advanced liver disease and potentially increasing mutation rates in affected patients.