Prolonged norovirus infections correlate to quasispecies evolution resulting in structural changes of surface-exposed epitopes

Suliman Qadir Afridi; Zainab Usman; Sainitin Donakonda; Jochen Martin Wettengel; Stoyan Velkov; Robert Beck; Markus Gerhard; Percy Knolle; Dmitrij Frishman; Ulrike Protzer; Hassan Moeini; Dieter Hoffmann

doi:10.1016/j.isci.2021.102802

Prolonged norovirus infections correlate to quasispecies evolution resulting in structural changes of surface-exposed epitopes

iScience. 2021 Jun 30;24(7):102802. doi: 10.1016/j.isci.2021.102802. eCollection 2021 Jul 23.

Authors

Suliman Qadir Afridi^{1

2}, Zainab Usman³, Sainitin Donakonda^{4

2}, Jochen Martin Wettengel¹, Stoyan Velkov¹, Robert Beck⁵, Markus Gerhard^{6

2}, Percy Knolle^{4

2}, Dmitrij Frishman³, Ulrike Protzer^{1

2}, Hassan Moeini^{1

2}, Dieter Hoffmann^{1

2}

Affiliations

¹ Institute of Virology, Technische Universität/Helmholtz Zentrum München, 81675 Munich, Germany.
² German Center for Infection Research (DZIF), Munich, Germany.
³ Department of Bioinformatics, Wissenschaftszentrum Weihenstephan, Technische Universität München, 85354 Freising, Germany.
⁴ Institute of Molecular Immunology and Experimental Oncology, Technische Universität München, 81675 Munich, Germany.
⁵ Institute of Medical Virology and Epidemiology of Viral diseases, Universitäts Klinikum Tübingen, 72076 Tübingen, Germany.
⁶ Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany.

Abstract

In this study, we analyzed norovirus (NoV) evolution in sequential samples of six chronically infected patients. The capsid gene was amplified from stool samples, and deep sequencing was performed. The role of amino acid flexibility in structural changes and ligand binding was studied with molecular dynamics (MD) simulations. Concentrations of capsid-specific antibodies increased in sequential sera. Capsid sequences accumulated mutations during chronic infection, particularly in the surface-exposed antigenic epitopes A, D, and E. The number of quasispecies increased in infections lasting for >1 month. Interestingly, high genetic complexity and distances were followed by ongoing NoV replication, whereas lower genetic complexity and distances preceded cure. MD simulation revealed that surface-exposed amino acid substitutions of the P2 domain caused fluctuation of blockade epitopes. In conclusion, the capsid protein accumulates numerous mutations during chronic infection; however, only those on the protein surface change the protein structure substantially and may lead to immune escape.

Keywords: Molecular modeling; Virology.