Hepatitis B virus (HBV) and delta virus (HDV) interactions : effects of HDV replication on drug resistance, immune escape and HBeAg-negative mutants of HBV

摘要

Delta hepatitis, hepatitis D virus (HDV) co- or super-infection in hepatitis B virus (HBV) infected individuals, is the most severe form of chronic hepatitis. Although HDV oftentimes suppresses HBV replication, also high levels of HDV and HBV can persist in co-infected individuals. In this study I aimed at identifying functionally relevant molecular interactions between HBV and HDV. To investigate HBV and delta virus interactions, I analysed the HDV full-length genome as well as the entire HDV protein (HDAg) coding sequences of 34 HDV-infected Iranian patients. I also conducted a case-control analysis to compare the HBV genome of 17 HBV/HDV co-infected patients with detectable HBV-DNA in their serum with a control group of HBV mono-infected individuals (34 sequences) for mutations in S-HBsAg, reverse transcriptase (rt) domain and precore (PC) or basal core promoter (BCP) regions. The functional effects of commonly observed HBV mutations, including Lamivudine (LAM)-resistance mutations (rtM204V/I and rtL180M) alone and together with immune escape mutants (sP120T, sG145R), PC (G1896A) and BCP (A1762T/G1764A) mutations, on the replicative capacity of both HBV and HDV, were also investigated.Phylogenetic analyses of full-length HDV and L-HDAg isolates revealed that all strains clustered with genotype 1. I also observed several non-synonymous mutations that affected immunogenic epitopes of L-HDAg towards CD8 T-cell- and B-cell-driven immune responses. Among the consecutive HBV/HDV infected patients (71 serum samples), 24 had detectable HBV replication with successful HBV sequencing in 17 cases. HBV genotype D was detected in HDV-infected patients, alongside characteristic amino acid substitutions in cytosolic domains (CYL-I and II) of HBsAg. On a functional level, HDV co-infection did not affect replication of HBV polymerase or immune escape mutants, but significantly reduced replicative capacity of strains containing PC or BCP mutations. HBV polymerase or surface antigen mutants affected HDV replication in vitro. In conclusion this study revealed functional interactions between HBV mutants and HDV, in line with a distinct mutational pattern of HDV and HBV in co-infected patients.