Human low-density lipoprotein receptor plays an important role in hepatitis B virus infection

Hepatitis B virus (HBV) chronically infects more than 240 million people worldwide, resulting in chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV vaccine is effective to prevent new HBV infection but does not offer therapeutic benefit to hepatitis B patients. Neither are current antiviral drugs curative of chronic hepatitis B. A more thorough understanding of HBV infection and replication holds a great promise for identification of novel antiviral drugs and design of optimal strategies towards the ultimate elimination of chronic hepatitis B. Recently, we have developed a robust HBV cell culture system and discovered that human apolipoprotein E (apoE) is enriched on the HBV envelope and promotes HBV infection and production. In the present study, we have determined the role of the low-density lipoprotein receptor (LDLR) in HBV infection. A LDLR-blocking monoclonal antibody potently inhibited HBV infection in HepG2 cells expressing the sodium taurocholate cotransporting polypeptide (NTCP) as well as in primary human hepatocytes. More importantly, small interfering RNAs (siRNAs)-mediated knockdown of LDLR expression and the CRISPR/Cas9-induced knockout of the LDLR gene markedly reduced HBV infection. A recombinant LDLR protein could block heparin-mediated apoE pulldown, suggesting that LDLR may act as an HBV cell attachment receptor via binding to the HBV-associated apoE. Collectively, these findings demonstrate that LDLR plays an important role in HBV infection probably by serving as a virus attachment receptor. Author summary Requirement of multiple cell surface receptors and co-receptors for efficient virus infection is exemplified by human immunodeficient virus (HIV) and hepatitis C virus (HCV). In the case of HBV, expression of the NTCP receptor alone in human and murine hepatocytes converted HBV susceptibility albeit at low levels. Recent identification of the glypican 5 (GPC5) and epidermal growth factor receptor (EGFR) as HBV infection-promoting factors suggests that efficient HBV infection requires multiple cell surface molecules as virus attachment and post-attachment receptors. Here, we provide substantial evidence demonstrating that another cell surface receptor LDLR plays an important role in HBV infection. Downregulation of LDLR expression significantly lowered HBV infection, whereas its upregulation promoted HBV infection. The levels of LDLR expression correlated with HBV cell attachment, suggesting that it serves as an HBV cell attachment receptor. The inhibition of heparin-mediated apoE pulldown by a purified LDLR suggested that LDLR promotes HBV infection probably through its binding to HBV-associated apoE. It is warranted to further determine whether other LDLR family members also play a role in HBV infection.

Automated summary

HBV infection is a major global health issue, with current treatments being limited. Recent research has shown that LDLR plays a crucial role in HBV infection, suggesting potential new avenues for HBV therapy. Further studies are needed to explore the involvement of other LDLR family members in HBV infection.