Identification of naturally occurring monoclonal antibody escape variants of louping ill virus

Gao, George F.; Hussain, Mohammed Hassan; Reid, H.W.; Gould, Ernest A.

doi:10.1099/0022-1317-75-3-609

Cited by 36 publications

(30 citation statements)

References 33 publications

(35 reference statements)

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“…Clearly, this mutation also eliminates the 308-311 salt bridge, but this was apparently tolerated by the virus. It was reported previously that mutations at position 308 strongly impaired the neurovirulence of the closely related LI virus (3,9). Our data only partially support this observation.…”

Section: Discussionsupporting

confidence: 56%

“…Aside from dengue type 2 virus, for which a requirement for heparan sulfate binding has been demonstrated (2), no specific flavivirus cellular receptors have been definitively identified, but some reports indicate the presence of various cell surface proteins with specific binding affinities for different flaviviruses (10,11,19,27). An involvement of the lateral surface of domain III in cell attachment is suggested by several lines of indirect evidence (12,22), including the immunoglobulin-like fold of this domain, which is characteristically found in many proteins with specific binding functions, the high density of charged surface residues on the lateral surface, the presence of an RGD motif in some mosquito-borne flaviviruses (which is known in other cases to be recognized by members of the integrin protein familiy), and the identification of mutations in this region in host range mutants (14) and mutants with altered virulence properties (1,3,4,8,9,13,26). In this study we introduced mutations at four positions (residues 308 to 311) of the upper-lateral surface of domain III of the TBE virus protein E and investigated their influence on biological properties of the resulting mutant viruses.…”

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confidence: 99%

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Attenuation of Tick-Borne Encephalitis Virus by Structure-Based Site-Specific Mutagenesis of a Putative Flavivirus Receptor Binding Site

Mandl

Allison

Holzmann

et al. 2000

J Virol

127

103

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The impact of a specific region of the envelope protein E of tick-borne encephalitis (TBE) virus on the biology of this virus was investigated by a site-directed mutagenesis approach. The four amino acid residues that were analyzed in detail (E308 to E311) are located on the upper-lateral surface of domain III according to the X-ray structure of the TBE virus protein E and are part of an area that is considered to be a potential receptor binding determinant of flaviviruses. Mutants containing single amino acid substitutions, as well as combinations of mutations, were constructed and analyzed for their virulence in mice, growth properties in cultured cells, and genetic stability. The most significant attenuation in mice was achieved by mutagenesis of threonine 310. Combining this mutation with deletion mutations in the 3-noncoding region yielded mutants that were highly attenuated. The biological effects of mutation Thr 310 to Lys, however, could be reversed to a large degree by a mutation at a neighboring position (Lys 311 to Glu) that arose spontaneously during infection of a mouse. Mutagenesis of the other positions provided evidence for the functional importance of residue 308 (Asp) and its charge interaction with residue 311 (Lys), whereas residue 309 could be altered or even deleted without any notable consequences. Deletion of residue 309 was accompanied by a spontaneous second-site mutation (Phe to Tyr) at position 332, which in the three-dimensional structure of protein E is spatially close to residue 309. The information obtained in this study is relevant for the development of specific attenuated flavivirus strains that may serve as future live vaccines.Tick-borne encephalitis (TBE) virus is a human pathogenic member of the genus Flavivirus (family Flaviviridae) (31). Many members of this genus can cause severe human diseases, the most important representatives besides TBE virus being the mosquito-borne viruses yellow fever (YF) virus, Japanese encephalitis (JE) virus, and the four serotypes of dengue virus (18). In spite of the availability of attenuated live vaccines (in the case of YF virus) and formalin-inactivated killed vaccines (TBE virus, JE virus) which have proven to be effective for the prevention of flavivirus infections, there is a strong demand for the development of novel and improved vaccines against these and other flavivirus infections. For the rational design of live vaccines, a detailed understanding of the molecular basis of virulence and pathogenesis is a major goal. With the availability of modern molecular techniques and high-resolution structural information, it is now possible to alter viral structures in a specific and rational way in order to understand structurefunction relationships. This knowledge can then be applied to achieve the desired biological property, such as attenuation of the virus.Flavivirus virions are relatively simple particles consisting of a nucleocapsid composed of a single capsid protein (C) surrounded by a lipid membrane that contains two viral protein...

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Section: Discussionsupporting

confidence: 56%

mentioning

confidence: 99%

Attenuation of Tick-Borne Encephalitis Virus by Structure-Based Site-Specific Mutagenesis of a Putative Flavivirus Receptor Binding Site

Mandl

Allison

Holzmann

et al. 2000

J Virol

127

103

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“…An amino acid mutation at amino acid E-303 (Lys ~ Gln) of yellow fever vaccine revertant P-16065 (equivalent to E-307 for JE virus) has been implicated in increased mouse neuroinvasiveness (Jennings et al, 1994) and has been confirmed by recombinant chimeric viruses (E. Wang & A. D. T. Barrett, unpublished). It has also been reported that an epitope containing amino acid E-308 (equivalent to E-305 for JE virus) played a significant role in determining the mouse pathogenic characteristics of louping ill virus (Jiang et aL, 1993;Gao et al, 1994). The amino acids between E-300 and E-390 belong to domain III of the E protein (Rey et al, 1995) which is proposed to be involved in tissue tropism and virus-host cell interactions (Holzmann et al, 1990;Lobigs et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Molecular differences between wild-type Japanese encephalitis virus strains of high and low mouse neuroinvasiveness

Barrett²

1996

Journal of General Virology

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“…Domain III is hypothesized to be the receptor-binding domain and is likely to be important in the determination of viral tropism (14,15,16,26). Mutation in this region has been associated with a neurovirulent 17D vaccine revertant (18), as well as with attenuation in other flaviviruses (3,10,12,17,19,20,21). The hamster viscerotropic Asibi/hamster p7 virus differs from the parental Asibi/hamster p0 at two amino acids within domain III: K323 and K331.…”

Section: Discussionmentioning

confidence: 99%

“…It is characterized by three distinct domains: domain I, the central domain; domain II, the dimerization domain; and domain III, the putative receptor-binding domain (26). Mutations in the flavivirus E protein have been implicated in alterations of viral tropism and virulence (3,10,12,17,18,19,20,21,23,(29)(30)(31).…”

mentioning

confidence: 99%

Molecular Characterization of a Hamster Viscerotropic Strain of Yellow Fever Virus

McArthur

Suderman

Mutebi

et al. 2003

J Virol

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A hamster viscerotropic strain of yellow fever (YF) virus has been derived after serial passage of strain Asibi through hamsters. The parental Asibi/hamster p0 virus causes a mild and transient viremia in hamsters with no outward, clinical signs of illness. In contrast, the viscerotropic Asibi/hamster p7 virus causes a robust viremia, severe illness, and death in subadult hamsters. The genome of the hamster viscerotropic Asibi/ hamster p7 virus has been sequenced and compared with the parental nonviscerotropic Asibi/hamster p0 virus identifying 14 nucleotide changes encoding only seven amino acid substitutions. The majority of these substitutions (five of seven) fall within the envelope (E) protein at positions Q27H, D28G, D155A, K323R, and K331R. These results support an important role for the E protein in determining YF virus viscerotropism.

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Identification of naturally occurring monoclonal antibody escape variants of louping ill virus

Cited by 36 publications

References 33 publications

Attenuation of Tick-Borne Encephalitis Virus by Structure-Based Site-Specific Mutagenesis of a Putative Flavivirus Receptor Binding Site

Attenuation of Tick-Borne Encephalitis Virus by Structure-Based Site-Specific Mutagenesis of a Putative Flavivirus Receptor Binding Site

Molecular differences between wild-type Japanese encephalitis virus strains of high and low mouse neuroinvasiveness

Molecular Characterization of a Hamster Viscerotropic Strain of Yellow Fever Virus

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