Basic residues in hypervariable region 1 of hepatitis C virus envelope glycoprotein e2 contribute to virus entry

Area of Science:

• Virology
• Molecular Biology
• Structural Biology

Background:

• The N terminus of hepatitis C virus (HCV) envelope glycoprotein E2 contains a hypervariable region (HVR1).
• HVR1 is proposed to play a role in viral entry and exhibits significant amino acid variability.
• Despite variability, HVR1 generally displays basic residues at specific positions.

Purpose of the Study:

• To investigate the role of basic residues in HVR1 of HCV E2 glycoprotein in viral entry.
• To determine the genotype-dependent frequency of basic residues at specific positions within HVR1.
• To analyze the impact of HVR1 basic residue modifications on interactions with potential HCV receptors.

Main Methods:

• Analysis of a large dataset of HVR1 sequences to assess residue frequencies.
• Utilized retroviral pseudotyped particles (HCVpp) with genotype 1a envelope glycoproteins.
• Mutagenesis of HVR1 basic residues and assessment of HCVpp infectivity and receptor interactions (CD81, heparan sulfates, SR-BI).

Main Results:

• HVR1 basic residue frequency is genotype-dependent.
• HCVpp infectivity increased with the number of basic residues in HVR1; positional shifts also modulated infectivity.
• Mutations did not affect CD81 recognition or heparan sulfate involvement; no correlation with SR-BI ligand enhancement was observed.

Conclusions:

• The presence of basic residues in HVR1 significantly facilitates hepatitis C virus entry.
• While specific positions matter, the overall number of basic residues is crucial for infectivity.
• Known receptors like CD81, heparan sulfates, and SR-BI do not appear to be directly modulated by HVR1 basicity in this context.