Length polymorphisms in the hypervariable region-1 of hepatitis C virus E2: a novel regulator of viral entry and neutralisation

Devlin, Stephen (2026) Length polymorphisms in the hypervariable region-1 of hepatitis C virus E2: a novel regulator of viral entry and neutralisation. PhD thesis, University of Glasgow.

Abstract

Currently 50 million people globally are living with Hepatitis C Virus (HCV). Whilst direct-acting antivirals offer a cure, there is no vaccine for HCV. One major barrier to the development of an effective HCV vaccine is the lack of mechanistic understanding of E1E2, the HCV viral entry proteins. Of particular importance for vaccine design is the Hypervariable Region-1 (HVR-1) of the E2 glycoprotein. HVR-1 is an intrinsically disordered tail which mediates entry and immune evasion through an unknown mechanism. Through state-of-the-art machine learning-enabled protein structure prediction, bioinformatic analysis, and in vitro experiments, we investigated how length polymorphisms in the HVR- 1 contribute to phenotype.

We analysed 30,289 sequences covering >25 % of the E2 protein. To examine distribution of length polymorphisms across HCV genotypes, 9,103 unique HVR-1 sequences were extracted from this dataset and assessed. To evaluate HVR-1 conformation, we modelled 105 E2 proteins, and 96 E1E2 protein complexes using different protein structure prediction software platforms. To investigate how length polymorphisms in the HVR-1 affect virus phenotype, we cloned HVR- 1s of varying length into the prototypical J6 HCV to produce HCV pseudoparticles (HCVpp). We evaluated the infectivity, receptor dependency, and antibody sensitivity of this panel of HCVpp. Moreover, we produced sE2 proteins with the same length polymorphisms in the HVR-1 and interrogated their ability to bind SR-B1.

This study found that the HVR-1 is predicted to be positioned in distinct conformations, length polymorphisms are common across all HCV genotypes, and length polymorphisms can modulate infectivity, receptor dependency, and neutralisation. Additionally, the sE2 experiments demonstrated that SR-B1 dependency and SR-B1 binding are uncoupled. These data allowed us to pull apart some of the molecular mechanism of the HVR-1. Altogether, this work suggests that the ability of the HVR-1 to adopt certain conformational states may correlate with phenotype. Moreover, length polymorphisms represent one way for HCV to fine tune the function of the HVR-1.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from the Medical Research Council, grant award MC_ST_CVR_2019.
• Subjects: Q Science > QR Microbiology > QR355 Virology
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Funder's Name: Medical Research Council
• Supervisor's Name: Grove, Professor Joe and Hutchinson, Professor Edward
• Date of Award: 2026
• Depositing User: Theses Team
• Unique ID: glathesis:2026-86281
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 29 Oct 2026 11:21
• Last Modified: 03 Nov 2026 09:42
• Thesis DOI: 10.5525/gla.thesis.86281
• URI: https://theses.gla.ac.uk/id/eprint/86281

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