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  1. Article ; Online: GB Virus B and Hepatitis C Virus, Distantly Related Hepaciviruses, Share an Entry Factor, Claudin-1.

    Toon, Kamilla / Kalemera, Mphatso D / Palor, Machaela / Rose, Nicola J / Takeuchi, Yasuhiro / Grove, Joe / Mattiuzzo, Giada

    Journal of virology

    2023  Volume 97, Issue 7, Page(s) e0046923

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

    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
    MeSH term(s) Animals ; Humans ; Hepacivirus/genetics ; GB virus B ; Claudin-1/genetics ; Hepatitis C
    Chemical Substances Claudin-1
    Language English
    Publishing date 2023-06-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.00469-23
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  2. Article ; Online: Optimized cell systems for the investigation of hepatitis C virus E1E2 glycoproteins.

    Kalemera, Mphatso D / Capella-Pujol, Joan / Chumbe, Ana / Underwood, Alexander / Bull, Rowena A / Schinkel, Janke / Sliepen, Kwinten / Grove, Joe

    The Journal of general virology

    2020  Volume 102, Issue 1

    Abstract: Great strides have been made in understanding and treating hepatitis C virus (HCV) thanks to the development of various experimental systems including cell-culture-proficient HCV, the HCV pseudoparticle system and soluble envelope glycoproteins. The HCV ... ...

    Abstract Great strides have been made in understanding and treating hepatitis C virus (HCV) thanks to the development of various experimental systems including cell-culture-proficient HCV, the HCV pseudoparticle system and soluble envelope glycoproteins. The HCV pseudoparticle (HCVpp) system is a platform used extensively in studies of cell entry, screening of novel entry inhibitors, assessing the phenotypes of clinically observed E1 and E2 glycoproteins and, most pertinently, in characterizing neutralizing antibody breadth induced upon vaccination and natural infection in patients. Nonetheless, some patient-derived clones produce pseudoparticles that are either non-infectious or exhibit infectivity too low for meaningful phenotyping. The mechanisms governing whether any particular clone produces infectious pseudoparticles are poorly understood. Here we show that endogenous expression of CD81, an HCV receptor and a cognate-binding partner of E2, in producer HEK 293T cells is detrimental to the infectivity of recovered HCVpp for most strains. Many HCVpp clones exhibited increased infectivity or had their infectivity rescued when they were produced in 293T cells CRISPR/Cas9 engineered to ablate CD81 expression (293T
    MeSH term(s) Antibody Affinity ; Gene Knockdown Techniques ; HEK293 Cells ; Hepacivirus/immunology ; Hepacivirus/physiology ; Hepatitis C/virology ; Hepatitis C Antibodies/immunology ; Hepatitis C Antigens/immunology ; Hepatitis C Antigens/metabolism ; Humans ; Mannose/chemistry ; Polysaccharides/chemistry ; Protein Binding ; Receptors, Virus/genetics ; Receptors, Virus/metabolism ; Tetraspanin 28/genetics ; Tetraspanin 28/metabolism ; Viral Envelope Proteins/chemistry ; Viral Envelope Proteins/immunology ; Viral Envelope Proteins/metabolism
    Chemical Substances CD81 protein, human ; E1 protein, Hepatitis C virus ; Hepatitis C Antibodies ; Hepatitis C Antigens ; Polysaccharides ; Receptors, Virus ; Tetraspanin 28 ; Viral Envelope Proteins ; glycoprotein E2, Hepatitis C virus (157184-61-7) ; Mannose (PHA4727WTP)
    Keywords covid19
    Language English
    Publishing date 2020-11-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001512
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  3. Article ; Online: An entropic safety catch controls hepatitis C virus entry and antibody resistance.

    Stejskal, Lenka / Kalemera, Mphatso D / Lewis, Charlotte B / Palor, Machaela / Walker, Lucas / Daviter, Tina / Lees, William D / Moss, David S / Kremyda-Vlachou, Myrto / Kozlakidis, Zisis / Gallo, Giulia / Bailey, Dalan / Rosenberg, William / Illingworth, Christopher J R / Shepherd, Adrian J / Grove, Joe

    eLife

    2022  Volume 11

    Abstract: E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically ...

    Abstract E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Thus, HVR-1 is akin to a safety catch that prevents premature triggering of E1E2 activity. Crucially, this mechanism is turned off by host receptor interactions at the cell surface to allow entry. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies. This discovery provides an explanation for the ability of HCV to persist in the face of continual immune assault and represents a novel regulatory mechanism that is likely to be found in other viral fusion machinery.
    MeSH term(s) Antibodies, Neutralizing ; Entropy ; Hepacivirus/genetics ; Hepacivirus/metabolism ; Hepatitis C ; Humans ; Viral Envelope Proteins/metabolism ; Virus Internalization
    Chemical Substances Antibodies, Neutralizing ; Viral Envelope Proteins
    Language English
    Publishing date 2022-07-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.71854
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  4. Article: Optimized cell systems for the investigation of hepatitis C virus E1E2 glycoproteins

    Kalemera, Mphatso D / Capella-Pujol, Joan / Chumbe, Ana / Underwood, Alexander / Bull, Rowena A / Schinkel, Janke / Sliepen, Kwinten / Grove, Joe

    J. gen. virol

    Abstract: Great strides have been made in understanding and treating hepatitis C virus (HCV) thanks to the development of various experimental systems including cell-culture-proficient HCV, the HCV pseudoparticle system and soluble envelope glycoproteins. The HCV ... ...

    Abstract Great strides have been made in understanding and treating hepatitis C virus (HCV) thanks to the development of various experimental systems including cell-culture-proficient HCV, the HCV pseudoparticle system and soluble envelope glycoproteins. The HCV pseudoparticle (HCVpp) system is a platform used extensively in studies of cell entry, screening of novel entry inhibitors, assessing the phenotypes of clinically observed E1 and E2 glycoproteins and, most pertinently, in characterizing neutralizing antibody breadth induced upon vaccination and natural infection in patients. Nonetheless, some patient-derived clones produce pseudoparticles that are either non-infectious or exhibit infectivity too low for meaningful phenotyping. The mechanisms governing whether any particular clone produces infectious pseudoparticles are poorly understood. Here we show that endogenous expression of CD81, an HCV receptor and a cognate-binding partner of E2, in producer HEK 293T cells is detrimental to the infectivity of recovered HCVpp for most strains. Many HCVpp clones exhibited increased infectivity or had their infectivity rescued when they were produced in 293T cells CRISPR/Cas9 engineered to ablate CD81 expression (293TCD81KO). Clones made in 293TCD81KO cells were antigenically very similar to their matched counterparts made parental cells and appear to honour the accepted HCV entry pathway. Deletion of CD81 did not appreciably increase the recovered titres of soluble E2 (sE2). However, we did, unexpectedly, find that monomeric sE2 made in 293T cells and Freestyle 293-F (293-F) cells exhibit important differences. We found that 293-F-produced sE2 harbours mostly complex-type glycans whilst 293T-produced sE2 displays a heterogeneous mixture of both complex-type glycans and high-mannose or hybrid-type glycans. Moreover, sE2 produced in 293T cells is antigenically superior; exhibiting increased binding to conformational antibodies and the large extracellular loop of CD81. In summary, this work describes an optimal cell line for the production of HCVpp and reveals that sE2 made in 293T and 293-F cells are not antigenic equals. Our findings have implications for functional studies of E1E2 and the production of candidate immunogens.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #910292
    Database COVID19

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  5. Article: Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2.

    Dicken, Samuel J / Murray, Matthew J / Thorne, Lucy G / Reuschl, Ann-Kathrin / Forrest, Calum / Ganeshalingham, Maaroothen / Muir, Luke / Kalemera, Mphatso D / Palor, Machaela / McCoy, Laura E / Jolly, Clare / Towers, Greg J / Reeves, Matthew B / Grove, Joe

    bioRxiv : the preprint server for biology

    2021  

    Abstract: The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their ... ...

    Abstract The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their evolutionary trajectories will guide current mitigation measures, future genetic surveillance and vaccination strategies. Here we examine virus entry by the B.1.1.7 lineage, commonly referred to as the UK/Kent variant. Pseudovirus infection of model cell lines demonstrate that B.1.1.7 entry is enhanced relative to the Wuhan-Hu-1 reference strain, particularly under low expression of receptor ACE2. Moreover, the entry characteristics of B.1.1.7 were distinct from that of its predecessor strain containing the D614G mutation. These data suggest evolutionary tuning of spike protein function. Additionally, we found that amino acid deletions within the N-terminal domain (NTD) of spike were important for efficient entry by B.1.1.7. The NTD is a hotspot of diversity across sarbecoviruses, therefore, we further investigated this region by examining the entry of closely related CoVs. Surprisingly, Pangolin CoV spike entry was 50-100 fold enhanced relative to SARS-CoV-2; suggesting there may be evolutionary pathways by which SARSCoV-2 may further optimise entry. Swapping the NTD between Pangolin CoV and SARS-CoV-2 demonstrates that changes in this region alone have the capacity to enhance virus entry. Thus, the NTD plays a hitherto unrecognised role in modulating spike activity, warranting further investigation and surveillance of NTD mutations.
    Language English
    Publishing date 2021-03-22
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.03.22.436468
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  6. Article ; Online: An Entropic Safety Catch Controls Hepatitis C Virus Entry and Antibody Resistance

    Stejskal, Lenka / Kalemera, Mphatso D. / Palor, Machaela / Walker, Lucas / Daviter, Tina / Lees, William D. / Moss, David S. / Kremyda-Vlachou, Myrto / Kozlakidis, Zisis / Rosenberg, William / Illingworth, Christopher J. R. / Shepherd, Adrian J. / Grove, Joe

    bioRxiv

    Abstract: E1 and E2 (E1E2), the entry proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically ... ...

    Abstract E1 and E2 (E1E2), the entry proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Crucially, to allow entry, this mechanism is turned off by host receptor interactions at the cell surface. Thus, HVR-1 is akin to a safety catch on E1E2 activity. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies.
    Keywords covid19
    Publisher BioRxiv
    Document type Article ; Online
    DOI 10.1101/2020.11.11.377218
    Database COVID19

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  7. Article ; Online: Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2

    Dicken, Samuel J / Murray, Matthew J / Thorne, Lucy G / Reuschl, Ann-Kathrin / Forrest, Calum / Ganeshalingham, Maaroothen / Muir, Luke / Kalemera, Mphatso D / Palor, Machaela / McCoy, Laura E / Jolly, Clare / Towers, Greg J / Reeves, Matthew / Grove, Joe

    bioRxiv

    Abstract: The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their ... ...

    Abstract The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic. Determining the fundamental biology of viral variants and understanding their evolutionary trajectories will guide current mitigation measures, future genetic surveillance and vaccination strategies. Here we examine virus entry by the B.1.1.7 lineage, commonly referred to as the UK/Kent variant. Pseudovirus infection of model cell lines demonstrate that B.1.1.7 entry is enhanced relative to the Wuhan-Hu-1 reference strain, particularly under low expression of receptor ACE2. Moreover, the entry characteristics of B.1.1.7 were distinct from that of its predecessor strain containing the D614G mutation. These data suggest evolutionary tuning of spike protein function. Additionally, we found that amino acid deletions within the N-terminal domain (NTD) of spike were important for efficient entry by B.1.1.7. The NTD is a hotspot of diversity across sarbecoviruses, therefore, we further investigated this region by examining the entry of closely related CoVs. Surprisingly, Pangolin CoV spike entry was 50-100 fold enhanced relative to SARS-CoV-2; suggesting there may be evolutionary pathways by which SARS-CoV-2 may further optimise entry. Swapping the NTD between Pangolin CoV and SARS-CoV-2 demonstrates that changes in this region alone have the capacity to enhance virus entry. Thus, the NTD plays a hitherto unrecognised role in modulating spike activity, warranting further investigation and surveillance of NTD mutations.
    Keywords covid19
    Language English
    Publishing date 2021-03-22
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.03.22.436468
    Database COVID19

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  8. Article ; Online: Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike.

    Cantoni, Diego / Murray, Matthew J / Kalemera, Mphatso D / Dicken, Samuel J / Stejskal, Lenka / Brown, Georgina / Lytras, Spyros / Coey, Jonathon D / McKenna, James / Bridgett, Stephen / Simpson, David / Fairley, Derek / Thorne, Lucy G / Reuschl, Ann-Kathrin / Forrest, Calum / Ganeshalingham, Maaroothen / Muir, Luke / Palor, Machaela / Jarvis, Lisa /
    Willett, Brian / Power, Ultan F / McCoy, Laura E / Jolly, Clare / Towers, Greg J / Doores, Katie J / Robertson, David L / Shepherd, Adrian J / Reeves, Matthew B / Bamford, Connor G G / Grove, Joe

    EMBO reports

    2022  Volume 23, Issue 10, Page(s) e54322

    Abstract: The emergence of SARS-CoV-2 variants has exacerbated the COVID-19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral transmission being responsible for attachment, receptor ... ...

    Abstract The emergence of SARS-CoV-2 variants has exacerbated the COVID-19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral transmission being responsible for attachment, receptor engagement and membrane fusion, and an important target of immunity. Variants frequently bear truncations of flexible loops in the N-terminal domain (NTD) of spike; the functional importance of these modifications has remained poorly characterised. We demonstrate that NTD deletions are important for efficient entry by the Alpha and Omicron variants and that this correlates with spike stability. Phylogenetic analysis reveals extensive NTD loop length polymorphisms across the sarbecoviruses, setting an evolutionary precedent for loop remodelling. Guided by these analyses, we demonstrate that variations in NTD loop length, alone, are sufficient to modulate virus entry. We propose that variations in NTD loop length act to fine-tune spike; this may provide a mechanism for SARS-CoV-2 to navigate a complex selection landscape encompassing optimisation of essential functionality, immune-driven antigenic variation and ongoing adaptation to a new host.
    MeSH term(s) COVID-19/genetics ; Humans ; Phylogeny ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics
    Chemical Substances Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2022-09-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.15252/embr.202154322
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