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

Yingying Li,Guangxiang Luo,Jianming Hu

doi:10.1371/journal.ppat.1009722

Yingying Li, Guangxiang Luo + Show 1 more

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https://doi.org/10.1371/journal.ppat.1009722

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Abstract

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.

Highlights

Hepatitis B virus (HBV) chronically infects more than 240 million people worldwide [1], resulting in common liver diseases such as hepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC)
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)
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

Summary

Introduction

Hepatitis B virus (HBV) chronically infects more than 240 million people worldwide [1], resulting in common liver diseases such as hepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Upon HBV cell entry and uncoating, the viral polymerase protein attached to the viral DNA genome is removed in the cytoplasm, resulting in a deproteinized relaxed circular DNA (DP rcDNA). The underlying molecular mechanism of cccDNA synthesis and maintenance in the nucleus remains largely unknown [9,10]. The viral mRNAs and pgRNA encode seven proteins such as three different forms (L, M, and S) of envelope proteins (HBs), preCore (HBe precursor), core (HBc), polymerase (P), and X protein (HBx). Very little is known about the underlying molecular mechanisms of HBV infection, morphogenesis, and egress due largely to the lack of bona fide cell culture models of HBV propagation

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