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Ruben J.G. Hulswit
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford

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Preprint content
Published: 25 May 2021 in bioRxiv
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Comparison of evolution among related viruses can provide insights into shared adaptive processes, for example following host switching to a mutual host species. Whilst phylogenetic methods can help identify mutations that may be important for evolutionary processes such as adaptation to a new host, these can be enhanced by positioning candidate mutations to known functional sites on protein structures. Over the past two decades, three zoonotic betacoronaviruses have significantly impacted human public health: SARS-CoV-1, MERS-CoV and SARS-CoV-2, whilst two other betacoronaviruses, HKU1 and OC43, have circulated endemically in the human population for over 100 years. In this study, we use a comparative approach to prospectively search for potentially evolutionarily-relevant mutations within the Orf1ab and S genes across betacoronavirus species that have demonstrated sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1 and SARS-CoV-2). We used a combination of molecular evolution methods to identify 30 sites that display evidence of homoplasy and/or stepwise evolution, that may be suggestive of adaptation across emerging and endemic betacoronaviruses. Of these, seven sites also display evidence of being selectively relevant. Drawing upon known protein structure data, we find that four of the identified mutations [18121 (exonuclease/27), 21623 (spike/21), 21635 (spike/25) and 23948 (spike/796), in SARS-CoV-2 genome coordinates] are proximal to regions of known functionality. Our results provide a molecular-level context for common evolutionary pathways that betacoronaviruses may undergo during adaptation to the human host.

ACS Style

Marina Escalera-Zamudio; Sergei L. Kosakovsky Pond; Natalia Martínez de la Viña; Bernardo Gutiérrez; Julien Thézé; Thomas A. Bowden; Oliver G. Pybus; Ruben J.G. Hulswit. Identification of site-specific evolutionary trajectories shared across human betacoronaviruses. bioRxiv 2021, 1 .

AMA Style

Marina Escalera-Zamudio, Sergei L. Kosakovsky Pond, Natalia Martínez de la Viña, Bernardo Gutiérrez, Julien Thézé, Thomas A. Bowden, Oliver G. Pybus, Ruben J.G. Hulswit. Identification of site-specific evolutionary trajectories shared across human betacoronaviruses. bioRxiv. 2021; ():1.

Chicago/Turabian Style

Marina Escalera-Zamudio; Sergei L. Kosakovsky Pond; Natalia Martínez de la Viña; Bernardo Gutiérrez; Julien Thézé; Thomas A. Bowden; Oliver G. Pybus; Ruben J.G. Hulswit. 2021. "Identification of site-specific evolutionary trajectories shared across human betacoronaviruses." bioRxiv , no. : 1.

Review
Published: 23 February 2021 in Viruses
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The Bunyavirales order accommodates related viruses (bunyaviruses) with segmented, linear, single-stranded, negative- or ambi-sense RNA genomes. Their glycoproteins form capsomeric projections or spikes on the virion surface and play a crucial role in virus entry, assembly, morphogenesis. Bunyavirus glycoproteins are encoded by a single RNA segment as a polyprotein precursor that is co- and post-translationally cleaved by host cell enzymes to yield two mature glycoproteins, Gn and Gc (or GP1 and GP2 in arenaviruses). These glycoproteins undergo extensive N-linked glycosylation and despite their cleavage, remain associated to the virion to form an integral transmembrane glycoprotein complex. This review summarizes recent advances in our understanding of the molecular biology of bunyavirus glycoproteins, including their processing, structure, and known interactions with host factors that facilitate cell entry.

ACS Style

Ruben Hulswit; Guido Paesen; Thomas Bowden; Xiaohong Shi. Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure. Viruses 2021, 13, 353 .

AMA Style

Ruben Hulswit, Guido Paesen, Thomas Bowden, Xiaohong Shi. Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure. Viruses. 2021; 13 (2):353.

Chicago/Turabian Style

Ruben Hulswit; Guido Paesen; Thomas Bowden; Xiaohong Shi. 2021. "Recent Advances in Bunyavirus Glycoprotein Research: Precursor Processing, Receptor Binding and Structure." Viruses 13, no. 2: 353.

Other
Published: 11 August 2020
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Rift Valley fever (RVF) is a viral haemorrhagic disease first discovered in Kenya in 1930. Numerous animal studies have demonstrated that protective immunity is acquired following RVF virus (RVFV) infection, and that this correlates with acquisition of virus neutralizing antibodies (nAb) that target the viral envelope glycoproteins. However, naturally acquired immunity to RVF in humans is poorly described. Here, we characterized the immune response to the viral envelope glycoproteins, Gn and Gc, in RVFV-exposed Kenyan adults. Long-lived IgG (dominated by IgG1 subclass) and T cell responses were detected against both Gn and Gc. However, antigen-specific antibody depletion experiments showed that Gn-specific antibodies dominate the RVFV nAb response. IgG avidity against Gn, but not Gc, correlated with nAb titers. These data are consistent with the greater level of immune accessibility of Gn on the viral envelope surface and confirm the importance of Gn as an integral component for RVF vaccine development.

ACS Style

Daniel Wright; Elizabeth R. Allen; Madeleine H.A. Clark; John N. Gitonga; Henry K. Karanja; Ruben Hulswit; Iona Taylor; Sumi Biswas; Jennifer Marshall; Damaris Mwololo; John Muriuki; Bernard Bett; Thomas A. Bowden; George M. Warimwe. Naturally acquired Rift Valley fever virus neutralizing antibodies predominantly target the Gn glycoprotein. 2020, 1 .

AMA Style

Daniel Wright, Elizabeth R. Allen, Madeleine H.A. Clark, John N. Gitonga, Henry K. Karanja, Ruben Hulswit, Iona Taylor, Sumi Biswas, Jennifer Marshall, Damaris Mwololo, John Muriuki, Bernard Bett, Thomas A. Bowden, George M. Warimwe. Naturally acquired Rift Valley fever virus neutralizing antibodies predominantly target the Gn glycoprotein. . 2020; ():1.

Chicago/Turabian Style

Daniel Wright; Elizabeth R. Allen; Madeleine H.A. Clark; John N. Gitonga; Henry K. Karanja; Ruben Hulswit; Iona Taylor; Sumi Biswas; Jennifer Marshall; Damaris Mwololo; John Muriuki; Bernard Bett; Thomas A. Bowden; George M. Warimwe. 2020. "Naturally acquired Rift Valley fever virus neutralizing antibodies predominantly target the Gn glycoprotein." , no. : 1.

Preprint content
Published: 18 April 2020
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The intricate lattice of Gn and Gc glycoprotein spike complexes at the surface of hantaviruses facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Here, through study of a neutralizing monoclonal antibody (mAb 4G2) generated in a bank vole reservoir host following infection with Puumala virus (PUUV), we provide molecular-level insights into how antibody-mediated targeting of the hantaviral glycoprotein lattice effectively neutralizes the virus. Crystallographic analysis reveals that mAb 4G2 binds to a multi-domain site on Gc in the pre-fusion state, and that Fab binding is incompatible with the conformational changes of the Gc that are required for host cell entry. Cryo-electron microscopy of PUUV-like particles treated with Fab 4G2 demonstrates that the antibody binds to monomeric Gc at breaks in the Gn-Gc lattice, highlighting the immunological accessibility of Gc monomers on the mature hantavirus surface and the plastic nature of the higher-order lattice assembly. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.

ACS Style

Ilona Rissanen; Robert Stass; Stefanie A. Krumm; Jeffrey Seow; Ruben J.G. Hulswit; Guido C. Paesen; Jussi Hepojoki; Olli Vapalahti; Ake Lundkvist; Olivier Reynard; Viktor Volchkov; Katie J. Doores; Juha T. Huiskonen; Thomas A. Bowden. Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody. 2020, 1 .

AMA Style

Ilona Rissanen, Robert Stass, Stefanie A. Krumm, Jeffrey Seow, Ruben J.G. Hulswit, Guido C. Paesen, Jussi Hepojoki, Olli Vapalahti, Ake Lundkvist, Olivier Reynard, Viktor Volchkov, Katie J. Doores, Juha T. Huiskonen, Thomas A. Bowden. Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody. . 2020; ():1.

Chicago/Turabian Style

Ilona Rissanen; Robert Stass; Stefanie A. Krumm; Jeffrey Seow; Ruben J.G. Hulswit; Guido C. Paesen; Jussi Hepojoki; Olli Vapalahti; Ake Lundkvist; Olivier Reynard; Viktor Volchkov; Katie J. Doores; Juha T. Huiskonen; Thomas A. Bowden. 2020. "Molecular rationale for hantavirus neutralization by a reservoir host-derived monoclonal antibody." , no. : 1.