Promotion of hepatitis B virus infection by extracellular apolipoprotein E

Chronic hepatitis B virus (HBV) infection remains a major burden to global health, affecting more than 250 million people worldwide. HBV and host interactions determine the HBV chronicity. Our previous studies have found that human apolipoprotein E (apoE) is incorporated in infectious HBV virions and plays important roles in HBV infection and morphogenesis. ApoE mediates HBV cell attachment through its interaction with cell surface receptors such as the low-density lipoprotein receptor (LDLR) family members and heparan sulfate proteoglycans (HSPGs). More importantly, both HBV-associated apoE and its expression in hepatocytes are critical for efficient HBV infection. However, the importance of extracellular apoE in HBV infection has not been examined. In the present study, we have determined the role of extracellular apoE in HBV infection in vitro. ApoE is an exchangeable apolipoprotein and was found to be efficiently transferred to HBV virions when mixed with an apoE-null HBV, as suggested by the results obtained from coimmunoprecipitation experiments. More significantly, extracellular apoE3 lipoproteins significantly promoted HBV infection in a dose-dependent manner when mixed with apoE-null HBV prior to infection. The cell culture supernatants obtained from apoE3-overexpressing HepG2 cells, sera derived from human apoE3-knockin mice, and a purified recombinant apoE expressed in E. coli were all able to significantly promote HBV infection. Additionally, extracellular apoE3 lipoproteins could dose-dependently enhance HBV attachment to HepG2^NTCP cells. Collectively, these findings demonstrate that extracellular apoE3 plays a key role in HBV infection by exchangeable transfer to the HBV envelope and mediation of HBV cell attachment.

Human apolipoprotein E (apoE) is implicated in the infection of different viruses as an entry-promoting factor. Our previous studies have demonstrated that apoE is enriched in the envelopes of hepatitis B virus (HBV) and hepatitis C virus (HCV)and promotes their infection and morphogenesis in vitro. In the present study, we have uncovered a previously unrecognized role of extracellular apoE3 in the promotion of HBV infection. Extracellular apoE3 was efficiently transferred to the HBV envelope when incubated with an apoE-deficient HBV. Strikingly, apoE-null HBV infection was proportionally enhanced by the increasing amounts of apoE3-containing mouse sera, as well as the supernatants of apoE3-overexpressing HepG2 cells. Likewise, a lipidated recombinant apoE3 significantly promoted HBV infection in a dose-dependent manner. Additionally, extracellular apoE3 promoted regular HBV infection. Moreover, extracellular apoE3 enhanced HBV cell attachment. These findings suggest that apoE3 lipoproteins with various densities in the plasma of chronic hepatitis B patients may play a key role in HBV infection and pathogenesis in vivo.