Background: A conundrum in the natural history of hepatitis B virus (HBV) infection is that the virus appears to rely on the production of HBV e antigen (HBeAg) protein for establishment of persistent infection. We aimed to address this knowledge gap by dissecting the causal consequences of HBeAg production in a mouse model of HBV infection.
Design: We compared and contrasted the viral kinetics, liver transcriptome, liver proteome and outcomes in mice hydrodynamically injected with wildtype hepatitis B virus (WT virus) and mice injected with two naturally occurring and clinically relevant mutant viruses, basal core promoter (BCP) and precore (PC) mutant virus, that are characterized by deficient (BCP mutant) or absent (PC mutant) HBeAg production.
Results: HBV mutants that were deficient in HBeAg production were attenuated in their ability to establish early robust infection compared to WT virus. These differences were still present in mice with abrogated tumor necrosis factor (TNF) or interferon gamma (IFN-gamma) signalling. However, mutants and WT virus were equivalent in establishing infection in mice that were deficient in type I interferon (IFN-I) signalling. Additionally, when HBeAg was supplied in trans through co-infection with WT virus, mutant virus was able to establish robust infection. Liver transcriptome and proteome data showed that HBeAg abrogates the early innate immune response by antagonizing IFN-I responses.
Conclusion: The data implicate HBeAg as an immune evasion strategy used by HBV to escape IFN-I responses. Our studies define the role of HBeAg in establishing HBV infection and we speculate as to why this protein may become a liability for the virus during the chronic stages of infection.