Multiple Amino Acid Substitutions in Hemagglutinin Are Necessary for Wild-Type MeaslesVirus To Acquire the Ability To Use Receptor CD46 Efficiently

Tahara, Maino; Takeda, Makoto; Seki, Fumio; Hanabusa, Takao; Yanagi, Yusuke

doi:10.1128/jvi.02449-06

Cited by 63 publications

(59 citation statements)

References 60 publications

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“…2). On the other hand, the key residues for interaction of MV-H (Ed) with CD46 (23,24,28) span the ␤3 to ␤5 sheets of the side face of the head domain and are located differently from the key residues at the SLAM-binding site (Fig. 3B).…”

Section: Resultsmentioning

confidence: 99%

“…The structure also suggests that extensive masking by sugars limits the availability of potential epitopes on the surface of The amino acid residues predicted to be involved in receptor binding (23,24,28) are shown in magenta (SLAM) and cyan/light blue (CD46, strong/weak effect). The color scheme used is the same as Fig.…”

Section: Structural and Functional Insights Into Antiviral Drug Desigmentioning

confidence: 99%

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Crystal structure of measles virus hemagglutinin provides insight into effective vaccines

Hanabusa¹,

Kajikawa

Maita

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Measles still remains a major cause of childhood morbidity and mortality worldwide. Measles virus (MV) vaccines are highly successful, but the mechanism underlying their efficacy has been unclear. Here we report the crystal structure of the MV attachment protein, hemagglutinin, responsible for MV entry. The receptorbinding head domain exhibits a cubic-shaped ␤-propeller structure and forms a homodimer. N-linked sugars appear to mask the broad regions and cause the two molecules forming the dimer to tilt oppositely toward the horizontal plane. Accordingly, residues of the putative receptor-binding site, highly conserved among MV strains, are strategically positioned in the unshielded area of the protein. These conserved residues also serve as epitopes for neutralizing antibodies, ensuring the serological monotype, a basis for effective MV vaccines. Our findings suggest that sugar moieties in the MV hemagglutinin critically modulate virus-receptor interaction as well as antiviral antibody responses, differently from sugars of the HIV gp120, which allow for immune evasion.x-ray crystallography paramyxovirus ͉ morbillivirus ͉ SLAM ͉ infectious disease ͉ paramyxovirus

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Section: Resultsmentioning

confidence: 99%

Section: Structural and Functional Insights Into Antiviral Drug Desigmentioning

confidence: 99%

Crystal structure of measles virus hemagglutinin provides insight into effective vaccines

Hanabusa¹,

Kajikawa

Maita

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

226

260

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“…The mutation E492G was also included because it has been shown to stabilize CD46 binding (H-D4-YG 49,50 ; Figure 3F). …”

Section: Of H/f-lv Binding To the Cd46 Receptormentioning

confidence: 99%

Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

et al. 2017

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“…Since CD46 is expressed in all human and monkey nucleated cells, MV vaccine strains can grow in many human and primate cell lines. Indeed, when the H protein of a wild-type strain of MV was exchanged with that of an MV vaccine strain, the resulting recombinant wild-type MV strain grew in many human and monkey cell lines (12,28,35).Although the receptor specificity of the H proteins of MV strains has been studied extensively, very little is known about the effect of the H protein on the in vivo tropism and attenuation of MV. Given that the H proteins of MV vaccine strains can use CD46 in addition to SLAM and nectin-4 as cellular receptors, recombinant MV strains bearing the H protein of MV vaccine strains may have an expanded in vivo tropism.…”

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confidence: 99%

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confidence: 99%

Wild-Type Measles Virus with the Hemagglutinin Protein of the Edmonston Vaccine Strain Retains Wild-Type Tropism in Macaques

Takeuchi

Nagata

Kato

et al. 2012

J Virol

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A major difference between vaccine and wild-type strains of measles virus (MV) in vitro is the wider cell specificity of vaccine strains, resulting from the receptor usage of the hemagglutinin (H) protein. Wild-type H proteins recognize the signaling lymphocyte activation molecule (SLAM) (CD150), which is expressed on certain cells of the immune system, whereas vaccine H proteins recognize CD46, which is ubiquitously expressed on all nucleated human and monkey cells, in addition to SLAM. To examine the effect of the H protein on the tropism and attenuation of MV, we generated enhanced green fluorescent protein (EGFP)-expressing recombinant wild-type MV strains bearing the Edmonston vaccine H protein (MV-EdH) and compared them to EGFP-expressing wild-type MV strains. In vitro, MV-EdH replicated in SLAM ؉ as well as CD46 ؉ cells, including primary cell cultures from cynomolgus monkey tissues, whereas the wild-type MV replicated only in SLAM ؉ cells. However, in macaques, both wild-type MV and MV-EdH strains infected lymphoid and respiratory organs, and widespread infection of MV-EdH was not observed. Flow cytometric analysis indicated that SLAM ؉ lymphocyte cells were infected preferentially with both strains. Interestingly, EGFP expression of MV-EdH in tissues and lymphocytes was significantly weaker than that of the wild-type MV. Taken together, these results indicate that the CD46-binding activity of the vaccine H protein is important for determining the cell specificity of MV in vitro but not the tropism in vivo. They also suggest that the vaccine H protein attenuates MV growth in vivo. Measles remains a major cause of childhood morbidity and mortality worldwide especially in developing countries in spite of significant progress in global measles control programs. Measles virus (MV), belonging to the genus Morbillivirus of the family Paramyxoviridae, is an enveloped virus with a nonsegmented negative-strand RNA genome (11). The MV genome encodes 6 structural proteins: the nucleocapsid (N), phospho (P), matrix (M), fusion (F), hemagglutinin (H), and large (L) proteins. Two envelope glycoproteins, the F and H proteins, initiate infection of the target cells via binding of the H protein to its cellular receptors. Therefore, the H protein is of primary importance for determining the cell specificity of MV (22).The Edmonston strain of MV was isolated in 1954 by using a primary culture of human kidney cells (7). The Edmonston strain was subsequently adapted in a variety of cells, including chicken embryo fibroblasts, to enable the production of attenuated live vaccines, which are currently used worldwide (27). These live, attenuated MV strains are safe and induce strong cellular and humoral immune responses against MV. The Edmonston vaccine strain is no longer pathogenic in monkey models (2, 7, 37, 39). In contrast, wild-type MV strains isolated and passaged in B95a cells induce clinical signs resembling those of human measles in experimentally infected cynomolgus and rhesus monkeys (15, 16).A major difference betwe...

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Multiple Amino Acid Substitutions in Hemagglutinin Are Necessary for Wild-Type MeaslesVirus To Acquire the Ability To Use Receptor CD46 Efficiently

Cited by 63 publications

References 60 publications

Crystal structure of measles virus hemagglutinin provides insight into effective vaccines

Crystal structure of measles virus hemagglutinin provides insight into effective vaccines

Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

Wild-Type Measles Virus with the Hemagglutinin Protein of the Edmonston Vaccine Strain Retains Wild-Type Tropism in Macaques

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