HCV E1 influences the fitness landscape of E2 and may enhance escape from E2-specific antibodies

Hang Zhang; Rowena A Bull; Ahmed Abdul Quadeer; Matthew R McKay

doi:10.1093/ve/vead068

HCV E1 influences the fitness landscape of E2 and may enhance escape from E2-specific antibodies

Virus Evol. 2023 Nov 18;9(2):vead068. doi: 10.1093/ve/vead068. eCollection 2023.

Authors

Hang Zhang¹, Rowena A Bull^{2

3}, Ahmed Abdul Quadeer^{1

4}, Matthew R McKay^{4

5}

Affiliations

¹ Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, SAR, China.
² School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia.
³ The Kirby Institute for Infection and Immunity, Sydney, NSW 2052, Australia.
⁴ Department of Electrical and Electronic Engineering, University of Melbourne, Parkville, VIC 3010, Australia.
⁵ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.

Abstract

The Hepatitis C virus (HCV) envelope glycoprotein E1 forms a non-covalent heterodimer with E2, the main target of neutralizing antibodies. How E1-E2 interactions influence viral fitness and contribute to resistance to E2-specific antibodies remain largely unknown. We investigate this problem using a combination of fitness landscape and evolutionary modeling. Our analysis indicates that E1 and E2 proteins collectively mediate viral fitness and suggests that fitness-compensating E1 mutations may accelerate escape from E2-targeting antibodies. Our analysis also identifies a set of E2-specific human monoclonal antibodies that are predicted to be especially resilient to escape via genetic variation in both E1 and E2, providing directions for robust HCV vaccine development.

Keywords: Hepatitis C virus; broadly neutralizing antibodies; envelope protein E1; envelope protein E2; evolutionary model; fitness landscape; inter-protein interactions; statistical inference.