Directed Mutagenesis of a Sindbis Virus Pathogenesis Site

Schoepp, Randal J.; Johnston, Robert E.

doi:10.1006/viro.1993.1111

Cited by 23 publications

(21 citation statements)

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“…Similar to our findings, previous work with other alphaviruses has also suggested that both structural and nonstructural genes are important for virulence (7,18,23,26,28,29,35,41,45,48,50,55,65). Most of these studies focused on the structural proteins, and in particular, the E2 glycoprotein.…”

Section: Discussionsupporting

confidence: 90%

Structural and Nonstructural Protein Genome Regions of Eastern Equine Encephalitis Virus Are Determinants of Interferon Sensitivity and Murine Virulence

Aguilar¹,

Adams

Wang

et al. 2008

J Virol

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Eastern equine encephalitis virus (EEEV) causes sporadic epidemics of human and equine disease in NorthAmerica, but South American strains have seldom been associated with human neurologic disease or mortality, despite serological evidence of infection. In mice, most North American and South American strains of EEEV produce neurologic disease that resembles that associated with human and equine infections. We identified a South American strain that is unable to replicate efficiently in the brain or cause fatal disease in mice yet produces 10-fold higher viremia than virulent EEEV strains. The avirulent South American strain was also sensitive to human interferon (

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Section: Discussionsupporting

confidence: 90%

Structural and Nonstructural Protein Genome Regions of Eastern Equine Encephalitis Virus Are Determinants of Interferon Sensitivity and Murine Virulence

Aguilar¹,

Adams

Wang

et al. 2008

J Virol

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“…Since one mechanism of loss of the ts phenotype is reversion of the nucleotide substitution to the wild-type assignment, we sought to modify the recombinant HPIV1 (rHPIV1) codons such that two or three nucleotide changes would be required to restore the wild-type amino acid coding assignment. This strategy has been employed previously to generate a set of attenuated recombinant Sindbis viruses bearing codon substitution mutations at several sites in the E2 virion protein (24,27). These recombinant viruses exhibited different levels of attenuation in vivo, but their phenotypic stability in vitro or in vivo was not explored.…”

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confidence: 99%

Codon Substitution Mutations at Two Positions in the L Polymerase Protein of Human Parainfluenza Virus Type 1 Yield Viruses with a Spectrum of Attenuation In Vivo and Increased Phenotypic Stability In Vitro

McAuliffe

Surman

Newman

et al. 2004

J Virol

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The Y942H and L992F temperature-sensitive (ts) and attenuating amino acid substitution mutations, previously identified in the L polymerase of the HPIV3cp45 vaccine candidate, were introduced into homologous positions of the L polymerase of recombinant human parainfluenza virus type 1 (rHPIV1). In rHPIV1, the Y942H mutation specified the ts phenotype in vitro and the attenuation (att) phenotype in hamsters, whereas the L992F mutation specified neither phenotype. Each of these codon mutations was generated by a single nucleotide substitution and therefore had the potential to readily revert to a codon specifying the wild-type amino acid residue. We introduced alternative amino acid assignments at codon 942 or 992 as a strategy to increase genetic stability and to generate mutants that exhibit a range of attenuation. Twenty-three recombinants with codon substitutions at position 942 or 992 of the L protein were viable. One highly ts and att mutant, the Y942A virus, which had a difference of three nucleotides from the codon encoding a wild-type tyrosine, also possessed a high level of genetic and phenotypic stability upon serial passage in vitro at restrictive temperatures compared to that of the parent Y942H virus, which possessed a single nucleotide substitution. We obtained mutants with substitutions at position 992 that, in contrast to the L992F virus, possessed the ts and att phenotypes. These findings identify the use of alternative codon substitution mutations as a method that can be used to generate candidate vaccine viruses with increased genetic stability and/or a modified level of attenuation.

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“…For Theiler's virus, demyelination, persistence and virulence have been mapped to the structural protein region of the genome (Brahic et al, 1991 ;Pritchard et al, 1993). For Sindbis virus, a togavirus like SFV, virulence for mice has been associated with a site on the E2 protein close to position 8902 (Polo & Johnston, 1991;Schoepp & Johnston, 1993) and with a single amino acid change in the E2 protein which controls binding to neural cells (Tucker & Griffin, 1991). Because of these previous results, our first approach was to analyse the nonconservative substitutions in the E2 gene.…”

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confidence: 99%

A single amino acid change in the E2 spike protein of a virulent strain of Semliki Forest virus attenuates pathogenicity

Glasgow

Killen

Liljeström

et al. 1994

Journal of General Virology

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The virulent strain SFV4 of Semliki Forest virus (SFV), produced from the infectious clone pSP6-SFV4, is lethal after intranasal (i.n.) infection of adult mice and for pregnant mice after intraperitoneal (i.p.) infection. In contrast, the A7 strain of SFV is avirulent when given i.n. to adult mice, but induces fetal death in pregnant mice after i.p. infection. The nucleotide and deduced amino acid sequences of part of the core and all of the envelope region of A7-SFV were determined and compared to those of SFV4. A7 differed from SFV4 at 80 nucleotides (nt) in the coding sequence, 15 of which were associated with amino acid differences and seven of which (two in the E2 protein and five in El) were nonconservative. The 3' non-coding sequence of A7 was longer (415 nt) than that of SFV4 (263 nt) and a divergent sequence of 181 nt was present adjacent to the end of the E1 coding region. The effects on virulence of two mutations in the E2 gene of SFV4, resulting in the non-conservative amino acid substitutions present in A7, were analysed. One mutation (mut 8729 a/c) resulted in only slight attenuation, whereas the other (mut 8902 a/g) resulted in avirulence for pregnant mice. However, mut 8902 a/g was lethal for the majority of developing fetuses after i.p. infection of the mother.

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Directed Mutagenesis of a Sindbis Virus Pathogenesis Site

Cited by 23 publications

References 0 publications

Structural and Nonstructural Protein Genome Regions of Eastern Equine Encephalitis Virus Are Determinants of Interferon Sensitivity and Murine Virulence

Structural and Nonstructural Protein Genome Regions of Eastern Equine Encephalitis Virus Are Determinants of Interferon Sensitivity and Murine Virulence

Codon Substitution Mutations at Two Positions in the L Polymerase Protein of Human Parainfluenza Virus Type 1 Yield Viruses with a Spectrum of Attenuation In Vivo and Increased Phenotypic Stability In Vitro

A single amino acid change in the E2 spike protein of a virulent strain of Semliki Forest virus attenuates pathogenicity

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