An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance

Stejskal, Lenka; Kalemera, Mphatso D; Palor, Machaela; Walker, Lucas; Daviter, Tina; Lees, William D.; Moss, David S.; Kremyda-Vlachou, Myrto; Kozlakidis, Zisis; Rosenberg, William; Illingworth, Christopher J. R.; Shepherd, Adrian J.; Grove, Joe

doi:10.1101/2020.11.11.377218

Cited by 1 publication

(2 citation statements)

References 94 publications

(124 reference statements)

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“…Based on this, the identified substitutions observed to decrease SR-BI entry dependency might promote direct viral engagement of CD81 by shifting E1/E2 conformations toward "open" states. This fits well with another recent study hypothesizing that E1/E2 hyperactivity is associated with HVR1 conformational entropy and/or dynamics [46]. They suggest that HVR1 acts as a safety catch with autoinhibitory functions that suppress the activity of E1/E2 on free virions.…”

Section: Plos Pathogenssupporting

confidence: 92%

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

et al. 2021

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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.

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Section: Plos Pathogenssupporting

confidence: 92%

“…They further hypothesize that SR-BI binds and stabilizes HVR1, whereby autoinhibition is relaxed and subsequent downstream HCV entry events can occur. Thus, it is proposed that HVR1 dynamics provide a potential molecular mechanism that links E1/E2 reactivity, SR-BI dependency, entry efficiency and NAb sensitivity [46].…”

Section: Plos Pathogensmentioning

confidence: 99%