Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

In vitro adaptation and characterization of attenuated hypervariable region 1 swap chimeras of hepatitis C virus

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Bacterial persisters in long-term infection: Emergence and fitness in a complex host environment

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Equine pegiviruses cause persistent infection of bone marrow and are not associated with hepatitis

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Hypermutation as an Evolutionary Mechanism for Achromobacter xylosoxidans in Cystic Fibrosis Lung Infection

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. The fading boundaries between patient and environmental routes of triazole resistance selection in Aspergillus fumigatus

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Inferior cure rate in pilot study of 4-week glecaprevir/pibrentasvir treatment with or without ribavirin of chronic hepatitis C

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Characterization of a Novel Hepatitis C Virus Genotype 1 Subtype from a Patient Failing 4 Weeks of Glecaprevir-Pibrentasvir Treatment

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Hepatitis C virus envelope protein dynamics and the link to hypervariable region 1

    Research output: Contribution to journalReviewResearchpeer-review

View graph of relations

Hepatitis C virus (HCV) chronically infects 70 million people worldwide with an estimated annual disease-related mortality of 400,000. A vaccine could prevent spread of this pervasive human pathogen, but has proven difficult to develop, partly due to neutralizing antibody evasion mechanisms that are inherent features of the virus envelope glycoproteins, E1 and E2. A central actor is the E2 motif, hypervariable region 1 (HVR1), which protects several non-overlapping neutralization epitopes through an incompletely understood mechanism. Here, we show that introducing different HVR1-isolate sequences into cell-culture infectious JFH1-based H77 (genotype 1a) and J4 (genotype 1b) Core-NS2 recombinants can lead to severe viral attenuation. Culture adaptation of attenuated HVR1-swapped recombinants permitted us to identify E1/E2 substitutions at conserved positions both within and outside HVR1 that increased the infectivity of attenuated HVR1-swapped recombinants but were not adaptive for original recombinants. H77 recombinants with HVR1 from multiple other isolates consistently acquired substitutions at position 348 in E1 and position 385 in HVR1 of E2. Interestingly, HVR1-swapped J4 recombinants primarily acquired other substitutions: F291I (E1), F438V (E2), F447L/V/I (E2) and V710L (E2), indicating a different adaptation pathway. For H77 recombinants, the adaptive E1/E2 substitutions increased sensitivity to the neutralizing monoclonal antibodies AR3A and AR4A, whereas for J4 recombinants, they increased sensitivity to AR3A, while having no effect on sensitivity to AR4A. To evaluate effects of the substitutions on AR3A and AR4A binding, we performed ELISAs on extracted E1/E2 protein and performed immunoprecipitation of relevant viruses. However, extracted E1/E2 protein and immunoprecipitation of HCV particles only reproduced the neutralization phenotypes of the J4 recombinants. Finally, we found that the HVR1-swap E1/E2 substitutions decrease virus entry dependency on co-receptor SR-BI. Our study identifies E1/E2 positions that could be critical for intra-complex HVR1 interactions while emphasizing the need for developing novel tools for molecular studies of E1/E2 interactions.

Original languageEnglish
Article numbere1009720
JournalP L o S Pathogens
Volume17
Issue number7
Pages (from-to)1-29
Number of pages29
ISSN1553-7366
DOIs
Publication statusPublished - Jul 2021

ID: 66871583