Specificity of Morbillivirus Hemagglutinins to Recognize SLAM of Different Species

Fukuhara, Hideo; Ito, Yuri; Sako, Miyuki; Kajikawa, Mizuho; Yoshida, Koki; Seki, Fumio; Mwaba, Mwila Hilton; Hanabusa, Takao; Higashibata, Masa Aki; Ose, Toyoyuki; Kuroki, Kazuhiko; Takeda, Makoto; Maenaka, Katsumi

doi:10.3390/v11080761

Cited by 24 publications

(32 citation statements)

References 31 publications

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“…In keeping with a recent report showing that CDV-H does not bind human SLAMF1 [ 28 ], we did not observe entry of MeV-Stealth-A09 into CHO-hSLAMF1 ( Fig 4F ). However, adaptation to human SLAMF1 via a different CDV strain has been observed [ 29 ].…”

Section: Resultssupporting

confidence: 92%

MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum

et al. 2021

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The frequent overexpression of CD46 in malignant tumors has provided a basis to use vaccine-lineage measles virus (MeV) as an oncolytic virotherapy platform. However, widespread measles seropositivity limits the systemic deployment of oncolytic MeV for the treatment of metastatic neoplasia. Here, we report the development of MeV-Stealth, a modified vaccine MeV strain that exhibits oncolytic properties and escapes antimeasles antibodies in vivo. We engineered this virus using homologous envelope glycoproteins from the closely-related but serologically non-cross reactive canine distemper virus (CDV). By fusing a high-affinity CD46 specific single-chain antibody fragment (scFv) to the CDV-Hemagglutinin (H), ablating its tropism for human nectin-4 and modifying the CDV-Fusion (F) signal peptide we achieved efficient retargeting to CD46. A receptor binding affinity of ~20 nM was required to trigger CD46-dependent intercellular fusion at levels comparable to the original MeV H/F complex and to achieve similar antitumor efficacy in myeloma and ovarian tumor-bearing mice models. In mice passively immunized with measles-immune serum, treatment of ovarian tumors with MeV-Stealth significantly increased overall survival compared with treatment with vaccine-lineage MeV. Our results show that MeV-Stealth effectively targets and lyses CD46-expressing cancer cells in mouse models of ovarian cancer and myeloma, and evades inhibition by human measles-immune serum. MeV-Stealth could therefore represent a strong alternative to current oncolytic MeV strains for treatment of measles-immune cancer patients.

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Section: Resultssupporting

confidence: 92%

MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum

et al. 2021

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“…proteins. However, many of the structural conclusions drawn from this work are based on assumptions that the RBD of all morbillivirus H proteins is structurally similar to the complex solved for MeV H and marmoset SLAM (maSLAM) [9], despite evidence that there may be subtle differences in the interaction site [10]. Our initial aim with this study was to use an unbiased mutagenic screening approach to confirm the importance of this proposed RBD of PPRV H for binding to the receptor SLAMF1.…”

Section: Accessmentioning

confidence: 93%

Application of error-prone PCR to functionally probe the morbillivirus Haemagglutinin protein

Gallo

Conceicao

Tsirigoti

et al. 2021

Journal of General Virology

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The enveloped morbilliviruses utilise conserved proteinaceous receptors to enter host cells: SLAMF1 or Nectin-4. Receptor binding is initiated by the viral attachment protein Haemagglutinin (H), with the viral Fusion protein (F) driving membrane fusion. Crystal structures of the prototypic morbillivirus measles virus H with either SLAMF1 or Nectin-4 are available and have served as the basis for improved understanding of this interaction. However, whether these interactions remain conserved throughout the morbillivirus genus requires further characterisation. Using a random mutagenesis approach, based on error-prone PCR, we targeted the putative receptor binding site for SLAMF1 interaction on peste des petits ruminants virus (PPRV) H, identifying mutations that inhibited virus-induced cell-cell fusion. These data, combined with structural modelling of the PPRV H and ovine SLAMF1 interaction, indicate this region is functionally conserved across all morbilliviruses. Error-prone PCR provides a powerful tool for functionally characterising functional domains within viral proteins.

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“…Models of mSLAM: CDV LN(10)1-H and rSLAM: CDV LN(10)1-H complexes were generated using the online tool SWISS-MODEL (https:// swissmodel.expasy.org/interactive#structure) and the MeV-H and maSLAM structures from PDB 3ALZ as templates ( 29 ). Three-dimensional (3D) models were constructed and visualized using PyMOL0.99rc2 (Schrödinger LLC, Delano, CA, USA) ( 30 ). The interaction between ligands of the protein complex was predicted using the online website PDBePISA ( http://www.ebi.ac.uk/msd-srv/prot_int/pistart.html ).…”

Section: Methodsmentioning

confidence: 99%

Mink SLAM V-Region V74I Substitutions Contribute to the Formation of Syncytia Induced by Canine Distemper Virus

Wang

Chen

et al. 2021

Front. Vet. Sci.

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The Signal lymphatic activation molecule (SLAM, also known as CD150) as the cellular receptor of canine distemper virus (CDV) plays an important role in the virus-host interaction. However, it is still unknown whether amino acid differences in the SLAM variable (V) region affect the formation of syncytia. Here, using raccoon dog SLAM (rSLAM) and mink SLAM (mSLAM), we performed SLAM-V homologous modeling, site-directed mutagenesis, and surface expression analysis, as well as a cell fusion assay, to study the interaction between SLAM and CDV. More specifically, our investigation focused on two amino acid residues (74 and 129) of SLAM, previously predicted to play a relevant role in receptor-ligand interaction. Our results indicated that only residues at position 60, 74, and 129 were different between rSLAM and mSLAM among the 29 amino acids that might interact with CDV H, and residues 74 and 129 were located in the interface region interacting with CDV H. The amino acid substitution at the positions of 74 have a significant effect on the expression of mSLAM. The SLAM-V74I mutation in mink significantly improved the cell fusion efficiency of CDV. In contrast, the SLAM-I74V mutation in the raccoon dog significantly decreased cell fusion efficiency. We conclude that residue 74 of SLAM plays an important role during the the formation of syncytia. Only when implementing CDV infection analysis, the rSLAM-Q129R can significantly decreased the mean number of syncytia, but the mSLAM-R129Q can't. Additionally, residue 60 show variability between rSLAM and mSLAM. We believe that our study makes a significant contribution to the literature because we provide molecular data, partially accounting for the differences in host membrane and virus interaction laying the foundation for further molecular work.

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Specificity of Morbillivirus Hemagglutinins to Recognize SLAM of Different Species

Cited by 24 publications

References 31 publications

MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum

MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum

Application of error-prone PCR to functionally probe the morbillivirus Haemagglutinin protein

Mink SLAM V-Region V74I Substitutions Contribute to the Formation of Syncytia Induced by Canine Distemper Virus

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