Hypervariable Region 1 Deletion and Required Adaptive Envelope Mutations Confer Decreased Dependency on Scavenger Receptor Class B Type I and Low-Density Lipoprotein Receptor for Hepatitis C Virus
0301 basic medicine
0303 health sciences
Tumor
Scavenger Receptors
Hepacivirus
Scavenger Receptors, Class B
Virus Internalization
Hepatitis C
Cell Line
LDL
Virus
3. Good health
03 medical and health sciences
Receptors, LDL
Viral Envelope Proteins
Cell Line, Tumor
Receptors
Humans
Receptors, Virus
Class B
Sequence Deletion
DOI:
10.1128/jvi.02017-13
Publication Date:
2013-11-21T03:15:58Z
AUTHORS (6)
ABSTRACT
ABSTRACT
Hypervariable region 1 (HVR1) of envelope protein 2 (E2) of hepatitis C virus (HCV) serves important yet undefined roles in the viral life cycle. We previously showed that the viability of HVR1-deleted JFH1-based recombinants with Core-NS2 of H77 (H77
ΔHVR1
, genotype 1a) and S52 (S52
ΔHVR1
, genotype 3a) in Huh7.5 cells was rescued by E2 substitutions N476D/S733F and an E1 substitution, A369V, respectively; HVR1-deleted J6 (J6
ΔHVR1
, genotype 2a) was fully viable. In single-cycle production assays, where HCV RNA was transfected into entry-deficient Huh7-derived S29 cells with low CD81 expression, we found no effect of HVR1 deletion on replication or particle release for H77 and S52. HCV pseudoparticle assays in Huh7.5 cells showed that HVR1 deletion decreased entry by 20- to 100-fold for H77, J6, and S52; N476D/S733F restored entry for H77
ΔHVR1
, while A369V further impaired S52
ΔHVR1
entry. We investigated receptor usage by antibody blocking and receptor silencing in Huh7.5 cells, followed by inoculation of parental and HVR1-deleted HCV recombinants. Compared to parental viruses, scavenger receptor class B type I (SR-BI) dependency was decreased for H77
ΔHVR1/N476D/S733F
, H77
N476D/S733F
, S52
ΔHVR1/A369V
, and S52
A369V
, but not for J6
ΔHVR1
. Low-density lipoprotein receptor (LDLr) dependency was decreased for HVR1-deleted viruses, but not for H77
N476D/S733F
and S52
A369V
. Soluble LDLr neutralization revealed strong inhibition of parental HCV but limited effect against HVR1-deleted viruses. Apolipoprotein E (ApoE)-specific HCV neutralization was similar for H77, J6, and S52 viruses with and without HVR1. In conclusion, HVR1 and HVR1-related adaptive envelope mutations appeared to be involved in LDLr and SR-BI dependency, respectively. Also, LDLr served ApoE-independent but HVR1-dependent functions in HCV entry.
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