LDLR and its role in Hepatitis B infection

Saakshi Bangera, DY Patil School of Biotechnology and Bioinformatics

HBV – Hepatitis B virus infects more than 200 million people around the world. The virus results in liver diseases such as hepatitis, cirrhosis, fibrosis, and hepatocellular carcinoma (HCC). Prophylactic HBV vaccine reduces the number of infections but fails to offer a therapeutic benefit to chronically infected people. Current antiviral therapies consisting of interferon (IFN) and nucleoside analogues (NAs) can suppress the viral replication but cannot cure the patient off of the virus. Prolonged HBV infection is the chief cause of hepatocellular carcinoma – the third leading cause of worldwide deaths due to cancer. Therefore, HBV infection poses a serious threat to global health. 

Hepatitis B virus consists of an enveloped, double-stranded DNA genome. Upon the entry of HBV in the cell and uncoating, the viral polymerase protein attached to the viral genome is released in the host cytoplasm.

The schematic representation shows exactly what causes the deproteinization of viral DNA.

This conversion is carried out by enzymes such as DNA polymerase, ligase, and damage repair systems. However, the mechanism of cccDNA synthesis is less researched. The cccDNA functions as a template for transcription of all viral RNAs (mRNAs and pgRNA). The viral mRNAs and pregenomic RNA (pgRNA) encode seven proteins like the three different forms (L, M, S) of –

• Envelope proteins (HBs)
• PreCore (HBe precursor)
• Core (HBc)
• Polymerase (P)
• X protein (HBx). 

The pgRNA and viral polymerase protein are encapsidated to form a nucleocapsid. 

Sodium taurocholate co-transporting polypeptide (NTCP) was discovered as the HBV receptor. This discovery has made it possible for the development of robust cell culture models of HBV infection. Using such cell culture systems, it was found that the human apolipoprotein E (apoE) is present in lots on the HBV envelope. It was also found that this protein is important for a successful HBV infection. mAb23 – an apoE-specific monoclonal antibody was able to capture HBV and block the infection effectively. ApoE expression silencing by using small interfering RNA (siRNA) or apoE gene knockout using CRISPR/Cas9. ApoE plays a key role in the transport, metabolism, and homeostasis of cholesterol and apoE-containing lipoproteins. ApoE does this by functioning as an important ligand for the low-density lipoprotein receptor (LDLR). The study hypothesizes that apoE stimulates HBV infection by binding to receptors like LDLR and HSPGS (heparan sulfate proteoglycans). 

HSPGs function in HBV cell attachment. Removal of HSPGs from the cell surface reduces the susceptibility of the cell to an HBV infection. Among the core proteins of HSPG, glypican 5 (GPC5) was discovered to be an HBV entry factor. 

This study aims to determine the role of LDLR in an HBV infection. 

Findings of the study

• LDLR-specific monoclonal antibody successfully blocked the HBV infection
• Down-regulation of LDLR expression weakened the HBV infection
• LDLR overexpression enhanced the infection
• Downregulation of LDLR expression failed to affect the DNA replication of HBV
• LDLR binds to the HBV-associated apoE to serve as an HBV cell attachment receptor

Conclusion

An LDLR-specific monoclonal antibody (C7) successfully blocked HBV infection in cell lines. Silencing of LDLR expression and its knockout by CRISPR/Cas9 effectively lowered HBV infection. Such findings propose that LDLR promotes HBV infection most likely through its contact with apoE present on the HBV envelope. Some of the other proteins belonging to the LDLR family may also play a part in HBV infection. Some examples might include VLDLR and LRPs (LDLR-related proteins). The detailed research about the mechanism of LDLR proteins in an HBV infection will provide us with knowledge about novel targets and antiviral development for eliminating chronic hepatitis B.

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Source: Li, Y., & Luo, G. (2021). Human low-density lipoprotein receptor plays an important role in hepatitis B virus infection. PLOS Pathogens, 17(7), e1009722. https://doi.org/10.1371/journal.ppat.1009722

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About the author

The author is currently pursuing MSc in Biotechnology from DY Patil School of Biotechnology and Bioinformatics. She believes that she doesn’t have a specific area of interest yet. She wishes to explore toxicology and food biotechnology. She’s quite passionate about Biotechnology and aims to grab every opportunity she comes across.