Decoding hepatitis B virus mutations that impact host-virus interactions and therapeutics

Hepatitis B virus (HBV), a lethal virus that results in the loss of two lives every minute, induces chronic and acute infections. Chronic infections may result in liver cirrhosis, which in turn may lead to hepatocellular carcinoma (HCC). Our study analysed 1,06,970 protein sequences of HBV genotypes (Gen A to H) from the HBV database (HBVdb) to construct position-specific scoring matrices. A total of 5,058 mutations were detected across all proteins, reflecting the notorious mutability of HBV. Among these, 2,658 significant mutations (sigmuts) with frequencies ranging between 10 and 80 were screened. Gen A presented the greatest number of sigmuts, whereas Gen H presented the least. Gen C, the most common HBV gene, featured 417 sigmuts, which we used for structural studies using DynaMut2 and molecular docking. We found that most core protein signatures significantly impact functions, including B-cell receptor binding and dimerisation. Interestingly, most sigmuts of the RNase H domain (694-843) of polymerase proteins promoted structural disorder, with possible impact on interactions with LINE-1 elements and progression to hepatocellular carcinoma. Intriguingly, despite the use of prominent nucleoside reverse transcriptase inhibitors (NRTIs) for over two decades, the drug-binding pockets of polymerase proteins have been found to be highly conserved. Nevertheless, since the long-term use of a few drugs as monotherapies has resulted in the development of drug resistance in recent years, we propose novel HBV targets for alternative therapeutic interventions.