Kamilla Toon

MRC University of Glasgow Centre for Virus Research

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Joe Grove

MRC University of Glasgow Centre for Virus Research

Michael R. Oliver

MRC University of Glasgow Centre for Virus Research

Giada Mattiuzzo

National Institute for Biological Standards and Control

Edward C. Holmes

University of Sydney

Machaela Palor

University College London

Vincenzo A. Costa

University of Sydney

Robert J. Gifford

MRC University of Glasgow Centre for Virus Research

Charlotte B. Lewis

MRC University of Glasgow Centre for Virus Research

Mphatso D. Kalemera

Imperial College London

Yasuhiro Takeuchi

Toranomon Hospital

Cooperative Institutions

MRC University of Glasgow Centre for Virus Research

University College London

National Institute for Biological Standards and Control

University of Sydney

Taronga Conservation Society Australia

Institute of Infection and Immunity

Centre for Immunity, Infection and Evolution

The Royal Free Hospital

University of Glasgow

Centre for Innovation in Regulatory Science

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GB Virus B and Hepatitis C Virus, Distantly Related Hepaciviruses, Share an Entry Factor, Claudin-1

Journal of Virology (2023)

Kamilla Toon Mphatso D. Kalemera Machaela Palor Nicola J. Rose Yasuhiro Takeuchi

Due to increased and broadened screening efforts, the last decade has seen a rapid expansion in the number of viral species classified into the

Liver Cancer

Hepatitis C

10.1128/jvi.00469-23

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Structures of the Hepaci-, Pegi-, and Pestiviruses envelope proteins suggest a novel membrane fusion mechanism

PLoS Biology (2023)

Michael R. Oliver Kamilla Toon Charlotte B. Lewis Stephen Devlin Robert J. Gifford

Enveloped viruses encode specialised glycoproteins that mediate fusion of viral and host membranes. Discovery and understanding of the molecular mechanisms of fusion have been achieved through structural analyses of glycoproteins from many different viruses, and yet the fusion mechanisms of some viral genera remain unknown. We have employed systematic genome annotation and AlphaFold modelling to predict the structures of the E1E2 glycoproteins from 60 viral species in the Hepacivirus, Pegivirus, and Pestivirus genera. While the predicted structure of E2 varied widely, E1 exhibited a very consistent fold across genera, despite little or no similarity at the sequence level. Critically, the structure of E1 is unlike any other known viral glycoprotein. This suggests that the Hepaci-, Pegi-, and Pestiviruses may possess a common and novel membrane fusion mechanism. Comparison of E1E2 models from various species reveals recurrent features that are likely to be mechanistically important and sheds light on the evolution of membrane fusion in these viral genera. These findings provide new fundamental understanding of viral membrane fusion and are relevant to structure-guided vaccinology.

Fusion mechanism

Herpesvirus glycoprotein B

Viral evolution

Virus classification

Viral membrane

10.1371/journal.pbio.3002174

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Citations (13)

Evidence of a novel viral membrane fusion mechanism shared by the Hepaci, Pegi and Pestiviruses

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Michael R. Oliver Kamilla Toon Charlotte B. Lewis Stephen Devlin Robert J. Gifford

Abstract Enveloped viruses encode specialised glycoproteins that mediate fusion of viral and host membranes. Discovery and understanding of the molecular mechanisms of fusion has been achieved through structural analyses of glycoproteins from many different viruses, and yet the fusion mechanisms of some viral genera remain unknown. We have employed systematic genome annotation and AlphaFold modelling to predict the structures of the E1E2 glycoproteins from sixty viral species in the Hepaci, Pegi and Pestivirus genera. Whilst the predicted structure of E2 varied widely, E1 exhibited a very consistent fold across genera, despite little or no homology at the sequence level. Critically, the structure of E1 is unlike any other known viral glycoprotein. This is the first evidence that the Hepaci, Pegi and Pestiviruses possess a common and novel membrane fusion mechanism. Comparison of E1E2 models from various species reveals recurrent features that are likely to be mechanistically important and sheds light on the evolution of membrane fusion in these viral genera. These findings provide new fundamental understanding of viral membrane fusion and are relevant to structure-guided vaccinology.

Fusion mechanism

Herpesvirus glycoprotein B

Viral membrane

Viral evolution

Virus classification

Homology

10.1101/2022.10.18.512720

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Citations (1)

Mapping glycoprotein structure reveals defining events in the evolution of theFlaviviridae

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Jonathon C.O. Mifsud Spyros Lytras Michael R. Oliver Kamilla Toon Vincenzo A. Costa

Summary Viral glycoproteins drive membrane fusion in enveloped viruses and determine host range, tissue tropism and pathogenesis. Despite their importance, there is a fragmentary understanding of glycoproteins within the Flaviviridae ; for many species the glycoproteins have not yet been identified, for others, such as the hepaciviruses, the molecular mechanisms of membrane fusion remain uncharacterised. Here, we combine comprehensive phylogenetic analyses with systematic protein structure prediction to survey glycoproteins across the entire Flaviviridae . We discover class-II fusion systems, homologous to the orthoflavivirus E glycoprotein, in most species, including highly-divergent jingmenviruses and large genome flaviviruses. However, the E1E2 glycoproteins of the hepaci-, pegi- and pestiviruses are structurally distinct, may represent a novel class of fusion mechanism, and are strictly associated with infection of vertebrate hosts. By mapping glycoprotein distribution onto the underlying phylogeny we reveal a complex history of evolutionary events that have shaped the diverse virology and ecology of the Flaviviridae .

Virus classification

Herpesvirus glycoprotein B

10.1101/2024.02.06.579159

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Citations (5)

More Than Just Gene Therapy Vectors: Lentiviral Vector Pseudotypes for Serological Investigation

Viruses (2021)

Kamilla Toon Emma M. Bentley Giada Mattiuzzo

Serological assays detecting neutralising antibodies are important for determining the immune responses following infection or vaccination and are also often considered a correlate of protection. The target of neutralising antibodies is usually located in the Envelope protein on the viral surface, which mediates cell entry. As such, presentation of the Envelope protein on a lentiviral particle represents a convenient alternative to handling of a potentially high containment virus or for those viruses with no established cell culture system. The flexibility, relative safety and, in most cases, ease of production of lentiviral pseudotypes, have led to their use in serological assays for many applications such as the evaluation of candidate vaccines, screening and characterization of anti-viral therapeutics, and sero-surveillance. Above all, the speed of production of the lentiviral pseudotypes, once the envelope sequence is published, makes them important tools in the response to viral outbreaks, as shown during the COVID-19 pandemic in 2020. In this review, we provide an overview of the landscape of the serological applications of pseudotyped lentiviral vectors, with a brief discussion on their production and batch quality analysis. Finally, we evaluate their role as surrogates for the real virus and possible alternatives.

10.3390/v13020217

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Citations (16)

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Kamilla Toon Mphatso D. Kalemera Machaela Palor Nicola J. Rose Yasuhiro Takeuchi

Abstract Due to increased and broadened screening efforts, the last decade has seen a rapid expansion in the number of viral species classified into the Hepacivirus genus. Conserved genetic features of hepaciviruses suggest they have undergone specific adaptation and evolved to hijack similar host proteins for efficient propagation in the liver. Here, we developed pseudotyped viruses to elucidate the entry factors of GB virus-B (GBV-B), the first hepacivirus described in an animal, closely related to hepatitis C virus (HCV). GBV-B pseudotyped viruses (GBVBpp) were shown to be uniquely sensitive to the serum of tamarins infected with GBV-B, validating their usefulness as a surrogate for GBV-B entry studies. We screened GBVBpp infection of hepatoma cell lines CRISPR/Cas9-engineered to ablate expression of individual HCV receptors/entry factors and found that claudin-1 is essential for GBV-B infection, indicating GBV-B and HCV share a common entry factor. Our data suggest that claudin-1 facilitates HCV and GBV-B entry through distinct mechanisms since the former requires the first extracellular loop and the latter is reliant on the second extracellular loop. The implication of this sharing of claudin-1 as an entry factor between these two hepaciviruses on their tissue tropism and evolutionary relationships will be discussed. Importance Hepatitis C virus (HCV) is a major public health burden; approximately 58 million individuals have chronic HCV infection which could lead to cirrhosis and liver cancer. To achieve the World Health Organisation target of eliminating hepatitis by 2030, new therapeutics and vaccines are needed. Understanding how HCV enters the cells will inform the design of new vaccines and treatments, targeting the first stage of HCV infection. However, the entry mechanism is complex and sparsely described. Studying the entry of related hepaciviruses will increase the knowledge of the molecular mechanisms of the first stages of HCV infection, such as the membrane fusion, and inform structure-guided HCV vaccine design; in this work we have identified a protein, Claudin-1, which facilitates the entry of HCV-related hepacivirus, but with a mechanism not described for HCV. Similar work on other hepaciviruses may unveil commonality of entry factors and possibly new mechanisms.

Host factors

Hepatitis C

Hepatitis B

10.1101/2022.08.10.503556

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Mapping glycoprotein structure reveals Flaviviridae evolutionary history

Nature (2024)

Jonathon C.O. Mifsud Spyros Lytras Michael R. Oliver Kamilla Toon Vincenzo A. Costa

Virus classification

Viral evolution

Herpesvirus glycoprotein B

10.1038/s41586-024-07899-8

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Citations (10)