共 51 条
[51]
World Health Organization, 2018, HEP C VIR FACT SHEET
Hypervariable region 1 and N-linked glycans of hepatitis C regulate virion neutralization by modulating envelope conformations
被引：46
作者：
Prentoe, Jannick
[1
,2
]
Velazquez-Moctezuma, Rodrigo
[1
,2
]
Augestad, Elias H.
[1
,2
]
Galli, Andrea
[1
,2
]
Wang, Richard
[3
]
Law, Mansun
[4
]
Alter, Harvey
[3
]
Bukh, Jens
[1
,2
]
机构：
[1] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis C Program, DK-2650 Hvidovre, Denmark
[2] Univ Copenhagen, Fac Hlth & Med Sci, Dept Immunol & Microbiol, DK-2200 Copenhagen, Denmark
[3] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA
[4] Scripps Res Inst, Dept Immunol & Microbiol, La Jolla, CA 92037 USA
来源：
关键词：
hepatitis C virus;
envelope protein 2;
neutralizing antibodies;
N-linked glycans;
envelope breathing;
VIRUS-ANTIBODIES;
GLYCOPROTEIN;
HCV;
PARTICLES;
DYNAMICS;
MECHANISM;
INFECTION;
EVASION;
ENTRY;
4A;
D O I：
10.1073/pnas.1822002116
中图分类号：
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号：
07 ;
0710 ;
09 ;
摘要：
About two million new cases of hepatitis C virus (HCV) infections annually underscore the urgent need for a vaccine. However, this effort has proven challenging because HCV evades neutralizing antibodies (NAbs) through molecular features of viral envelope glycoprotein E2, including hypervariable region 1 (HVR1) and N-linked glycans. Here, we observe large variation in the effects of removing individual E2 glycans across HCV strains H77(genotype 1a), J6(2a), and S52(3a) in Huh7.5 cell infections. Also, glycan-mediated effects on neutralization sensitivity were completely HVR1-dependent, and neutralization data were consistent with indirect protection of epitopes, as opposed to direct steric shielding. Indeed, the effect of removing each glycan was similar both in type (protective or sensitizing) and relative strength across four nonoverlapping neutralization epitopes. Temperature-dependent neutralization (e.g., virus breathing) assays indicated that both HVR1 and protective glycans stabilized a closed, difficult to neutralize, envelope conformation. This stabilizing effect was hierarchical as removal of HVR1 fully destabilized closed conformations, irrespective of glycan status, consistent with increased instability at acidic pH and high temperatures. Finally, we observed a strong correlation between neutralization sensitivity and scavenger receptor BI dependency during viral entry. In conclusion, our study indicates that HVR1 and glycans regulate HCV neutralization by shifting the equilibrium between open and closed envelope conformations. This regulation appears tightly linked with scavenger receptor BI dependency, suggesting a role of this receptor in transitions from closed to open conformations during entry. This importance of structural dynamics of HCV envelope glycoproteins has critical implications for vaccine development and suggests that similar phenomena could contribute to immune evasion of other viruses.
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页码：10039 / 10047
页数：9
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