Stejskal, Lenka ORCID: 0000-0002-4230-0963, Kalemera, Mphatso D., Lewis, Charlotte B., Palor, Machaela, Walker, Lucas, Daviter, Tina ORCID: 0000-0003-2636-5959, Lees, William D., Moss, David S., Kremyda-Vlachou, Myrto, Kozlakidis, Zisis ORCID: 0000-0002-3836-7209, Gallo, Giulia ORCID: 0000-0002-3269-142X, Bailey, Dalan, Rosenberg, William, Illingworth, Christopher J. R., Shepherd, Adrian J. and Grove, Joe ORCID: 0000-0001-5390-7579 (2022). An entropic safety catch controls hepatitis C virus entry and antibody resistance. eLife, 11. CAMBRIDGE: eLIFE SCIENCES PUBL LTD. ISSN 2050-084X

Full text not available from this repository.

Abstract

E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Thus, HVR-1 is akin to a safety catch that prevents premature triggering of E1E2 activity. Crucially, this mechanism is turned off by host receptor interactions at the cell surface to allow entry. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies. This discovery provides an explanation for the ability of HCV to persist in the face of continual immune assault and represents a novel regulatory mechanism that is likely to be found in other viral fusion machinery.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Stejskal, LenkaUNSPECIFIEDorcid.org/0000-0002-4230-0963UNSPECIFIED
Kalemera, Mphatso D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewis, Charlotte B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palor, MachaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, LucasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daviter, TinaUNSPECIFIEDorcid.org/0000-0003-2636-5959UNSPECIFIED
Lees, William D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moss, David S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kremyda-Vlachou, MyrtoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kozlakidis, ZisisUNSPECIFIEDorcid.org/0000-0002-3836-7209UNSPECIFIED
Gallo, GiuliaUNSPECIFIEDorcid.org/0000-0002-3269-142XUNSPECIFIED
Bailey, DalanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenberg, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Illingworth, Christopher J. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shepherd, Adrian J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grove, JoeUNSPECIFIEDorcid.org/0000-0001-5390-7579UNSPECIFIED
URN: urn:nbn:de:hbz:38-692198
DOI: 10.7554/eLife.71854
Journal or Publication Title: eLife
Volume: 11
Date: 2022
Publisher: eLIFE SCIENCES PUBL LTD
Place of Publication: CAMBRIDGE
ISSN: 2050-084X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BROADLY NEUTRALIZING ANTIBODIES; HYPERVARIABLE REGION 1; E2 ENVELOPE GLYCOPROTEIN; SCAVENGER RECEPTOR BI; CELL ENTRY; STRUCTURAL FLEXIBILITY; CONSERVED RESIDUES; MEMBRANE-FUSION; CD81; INFECTIONMultiple languages
BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69219

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item