Journal Article

Interplay between Basic Residues of Hepatitis C Virus Glycoprotein E2 with Viral Receptors, Neutralizing Antibodies and Lipoproteins

Dragun, Jakub, Pérez-del-Pulgar, Sofia, Mensa, Laura, Crespo, Gonzalo, Forns, Xavier, Koutsoudakis, George, Navasa, Miquel, González, Patricia, Coto-Llerena, Mairene

2012

Overview

Positively-charged amino acids are located at specific positions in the envelope glycoprotein E2 of the hepatitis C virus (HCV): two histidines (H) and four arginines (R) in two conserved WHY and one RGERCDLEDRDR motifs, respectively. Additionally, the E2 hypervariable region 1 (HVR1) is rich in basic amino acids. To investigate the role(s) of these residues in HCV entry, we subjected to comparative infection and sedimentation analysis cell culture-produced (HCVcc, genotype 2a) wild type virus, a panel of alanine single-site mutants and a HVR1-deletion variant. Initially, we analyzed the effects of these mutations on E2-heparan sulfate (HS) interactions. The positive milieu of the HVR1, formulated by its basic amino acids (key residues the conserved H³⁸⁶ and R⁴⁰⁸), and the two highly conserved basic residues H⁴⁸⁸ and R⁶⁴⁸ contributed to E2-HS interactions. Mutations in these residues did not alter the HCVcc-CD81 entry, but they modified the HCVcc-scavenger receptor class B type I (SR-BI) dependent entry and the neutralization by anti-E2 or patients IgG. Finally, separation by density gradients revealed that mutant viruses abolished partially or completely the infectivity of low density particles, which are believed to be associated with lipoproteins. This study shows that there exists a complex interplay between the basic amino acids located in HVR1 and other conserved E2 motifs with the HS, the SR-BI, and neutralizing antibodies and suggests that HCV-associated lipoproteins are implicated in these interactions.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptation / Alanine / Amino Acid Motifs / Amino Acid Sequence / Amino Acid Substitution / Amino acids / Amino Acids, Basic - chemistry / Antibodies / Antibodies, Neutralizing - pharmacology / Antibodies, Viral - pharmacology / Anticoagulants / Binding Sites / Blood lipids / CD81 antigen / Cell culture / Cell Line / Clonal deletion / Comparative analysis / Density gradients / Glycoprotein E2 / Glycoproteins / Health aspects / Hepacivirus - immunology / Hepacivirus - physiology / Heparan sulfate / Heparin - pharmacology / Hepatitis / Hepatitis C / Hepatitis C virus / Hepatitis C, Chronic - immunology / Hepatitis C, Chronic - virology / Host-Pathogen Interactions / Humans / Immunoglobulin G / Immunoglobulin G - pharmacology / Immunoglobulins / Infection / Infections / Infectivity / Lipoproteins / Lipoproteins - metabolism / Liver / Medicine / Molecular Sequence Data / Mutagenesis / Mutagenesis, Site-Directed / Mutants / Mutation / Neutralization / Neutralizing / Protein Binding / Proteins / Receptors / Residues / Scavenger receptors / Scavenger Receptors, Class B - metabolism / Sedimentation / Sulfate / Sulfates / Transplants & implants / Viral Envelope Proteins - chemistry / Viral Envelope Proteins - genetics / Viral Envelope Proteins - physiology / Virus Internalization - drug effects / Virus Replication - drug effects / Viruses