Hepatitis B Virus Genotypic Differences Map Structurally Close to NRTI Resistance Hot Spots

Despite the availability of a Hepatitis B Virus (HBV) vaccine, there are approximately 350 million people that are chronically infected with this virus that can cause liver cirrhosis and hepatocellular carcinoma. Currently, most approved anti-HBV drugs are nucleoside RT inhibitors (NRTIs) that target the viral enzyme reverse transcriptase (RT or P gene product). They suppress viral replication very efficiently but require long-term therapies, which invariably lead to the development of drug resistant viral strains with drug resistance mutations at the P gene. Because the reading frames of the P and S (surface antigen) genes partially overlap, selection of NRTI-resistance mutations may impart changes on the surface structural landscape of the virus. Conversely, genotypic differences on viral surface residues may also change the amino acid composition of the P gene and in terms affect HBV RT properties such as susceptibility to NRTIs. Interestingly, several studies have shown that patients infected with HBV from various genotypes respond differently to NRTI therapies. Here, we built a three-dimensional homology model of the catalytic core of HBV RT using HIV-1 RT as a template. We then mapped on the molecular model the residues that vary among various HBV genotypes. Surprisingly, the genotypic variability residues are generally in the vicinity of residues that are involved in NRTI resistance. Our results suggest that emergence of NRTI resistance mutations in HBV RT may be constrained by structural interactions with residues that vary among different genotypes.