Abstract
High genetic heterogeneity is an important characteristic of hepatitis C virus (HCV) that contributes to its ability to establish persistent infection. The hypervariable region 1 (HVR1) that includes the first 27 amino acid residues of the E2 envelope glycoprotein is the most variable region within the HCV polyprotein. HVR1 plays a major role in both HCV cell entry and immune evasion, but the respective contribution of specific amino acid residues is still unclear. Our mutagenesis analyses of HCV pseudoparticles and cell culture-derived HCV using the H77 isolate indicate that five residues at positions 14, 15, and 25-27 mediate binding of the E2 protein to the scavenger receptor class B, type I receptor, and any residue herein is indispensable for HCV cell entry. The region spanning positions 16-24 contains the sole neutralizing epitope and is dispensable for HCV entry, but it is involved in heparan binding. More importantly, this region is necessary for the enhancement of HCV entry by high density lipoprotein and interferes with virus neutralization by E2-neutralizing antibodies. Residues at positions 1-13 are also dispensable for HCV entry, but they can affect HCV infectivity by modulating binding of the envelope protein to scavenger receptor class B, type I. Mutations occurring at this site may confer resistance to HVR1 antibodies. These findings further our understanding about the mechanisms of HCV cell entry and the significance of HVR1 variation in HCV immune evasion. They have major implications for the development of HCV entry inhibitors and prophylactic vaccines.
Highlights
hypervariable region 1 (HVR1) spans 27 residues at the N terminus of the hepatitis C virus (HCV) envelope glycoprotein E2 and is the most variable region within the HCV polyprotein
Examination of the infectivity of the corresponding pseudoparticles in Huh7.5 cells indicated that HCV pseudoparticles (HCVpp) infectivity was decreased to less than 5% of the unmodified pseudoparticles by deletion of the entire HVR1 (⌬HVR1) and deletion of a single residue at positions 14, 15, 25, 26, or 27 reduced the infectivity by more than 85%
Using deletion mutagenesis and function analyses, we found that five aa residues (Ala-14, Gly-15, Lys-25, Gln-26, and Asn27) within the HVR1 of the H77 isolate play a key role in HCVpp entry
Summary
HVR1 spans 27 residues at the N terminus of the HCV envelope glycoprotein E2 and is the most variable region within the HCV polyprotein. Mutations occurring at this site may confer resistance to HVR1 antibodies These findings further our understanding about the mechanisms of HCV cell entry and the significance of HVR1 variation in HCV immune evasion. HCV has a high mutation rate that results from an error-prone RNA polymerase that yields genetically heterogeneous quasispecies that are characteristic of most infections [9, 10] These sequence variations are concentrated in specific regions of the genome, and the best characterized hypervariable region is the 27-amino acid residue component located at the N-terminal part of the envelope protein E2 (hypervariable region 1 (HVR1)) [11,12,13]. Our data show that HCV HVR1 contains three different functional microdomains that cooperate to confer HCV cell entry and immune evasion
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