Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
E-pub ahead of print

Identification of novel neutralizing determinants for protection against HCV

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Neutralization and receptor use of infectious culture-derived rat hepacivirus as a model for HCV

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Pathogenesis, MicroRNA-122 Gene-Regulation, and Protective Immune Responses After Acute Equine Hepacivirus Infection

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Letter to the Editor: Glucocorticosteroids for Alcohol-Associated Hepatitis

    Publikation: Bidrag til tidsskriftLetterForskningpeer review

  1. Two-component vaccine consisting of virus-like particles displaying hepatitis C virus envelope protein 2 oligomers

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Neutralization and receptor use of infectious culture-derived rat hepacivirus as a model for HCV

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Protection against SARS-CoV-2 transmission by a parenteral prime-Intranasal boost vaccine strategy

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Novel hepatitis B virus reverse transcriptase mutations in patients with sustained viremia despite long-term tenofovir treatment

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. Inactivated whole hepatitis C virus vaccine employing a licensed adjuvant elicits cross-genotype neutralizing antibodies in mice

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Vis graf over relationer

BACKGROUND AND AIMS: HCV evasion of neutralizing antibodies (nAb) results in viral persistence and poses challenges to the development of an urgently needed vaccine. N-linked glycosylation of viral envelope proteins is a key mechanism for such evasion. To facilitate rational vaccine design, we aimed to identify determinants of protection of conserved neutralizing epitopes.

APPROACH AND RESULTS: Using a reverse evolutionary approach, we passaged genotype 1a, 1b, 2a, 3a, and 4a HCV with envelope proteins (E1 and E2) derived from chronically infected patients without selective pressure by nAb in cell culture. Compared with the original viruses, HCV recombinants, engineered to harbor substitutions identified in polyclonal cell culture-passaged viruses, showed highly increased fitness and exposure of conserved neutralizing epitopes in antigenic regions 3 and 4, associated with protection from chronic infection. Further reverse genetic studies of acquired E1/E2 substitutions identified positions 418 and 532 in the N1 and N6 glycosylation motifs, localizing to adjacent E2 areas, as key regulators of changes of the E1/E2 conformational state, which governed viral sensitivity to nAb. These effects were independent of predicted glycan occupancy.

CONCLUSIONS: We show how N-linked glycosylation motifs can trigger dramatic changes in HCV sensitivity to nAb, independent of glycan occupancy. These findings aid in the understanding of HCV nAb evasion and rational vaccine design, as they can be exploited to stabilize the structurally flexible envelope proteins in an open conformation, exposing important neutralizing epitopes. Finally, this work resulted in a panel of highly fit cell culture infectious HCV recombinants.

OriginalsprogEngelsk
TidsskriftHepatology (Baltimore, Md.)
ISSN0270-9139
DOI
StatusE-pub ahead of print - 3 sep. 2022

Bibliografisk note

This article is protected by copyright. All rights reserved.

ID: 84474172