An attenuated mutant of Venezuelan encephalitis virus: Biochemical alterations and their genetic association with attenuation

Emini, Emilio A.; Wiebe, Michael E.

doi:10.1016/0042-6822(81)90020-9

Cited by 13 publications

(7 citation statements)

References 30 publications

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“…This variant, which will be described in detail elsewhere, retains the parental arginine at position 114 of E2, but carries an additional mutation in E2 that acts as a second-site reversion or suppressor mutation. In this context, it is important to note that other studies of alphavirus pathogenicity have shown that mutations affecting the El protein (29) or proteins involved in RNA synthesis (30) can lead to a measurable reduction of virulence. In summary, a study of closely related attenuated and virulent strains of Sindbis virus has identified a site in the E2 glycoprotein gene at which mutation leads simultaneously to reduced virulence in the neonatal mouse and accelerated penetration of cultured cells.…”

Section: Resultsmentioning

confidence: 99%

A single nucleotide change in the E2 glycoprotein gene of Sindbis virus affects penetration rate in cell culture and virulence in neonatal mice.

Davis¹,

Fuller²,

Dougherty³

et al. 1986

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

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The nucleotide sequence of the glycoprotein genes of fully virulent Sindbis virus and derived mutants that have reduced neurovirulence for neonatal mice (attenuated mutants) has been determined. A single amino acid difference, arginine instead of serine at position 114 of the mature E2 glycoprotein, distinguished the prototype attenuated mutant from its virulent wild-type parent. Virulent revertants of the attenuated mutant showed same-site reversion to the wild-type sequence. An identical single amino acid substitution, an arginine for the serine at E2 position 114, was found in a second independently selected attenuated mutant. The strains are characterized by genetic linkage between attenuation, accelerated penetration of baby hamster kidney cells, and efficient neutralization by the E2-specifilc monoclonal antibodies R6 and R13; selection for change in one property simultaneously selected for change in the other two (Olmsted, R. A., Baric, Sindbis virus, the prototype member of the alphavirus genus (1), has been well studied with respect to pathogenesis in animals and replication in cell culture. A single plaqueforming unit of the virus inoculated into a newborn mouse is sufficient to cause acute encephalitis and death within 5 days (2, 3). A relatively simple structure (4) and high degree of virulence for newborn mice, as well as relatedness to important human and veterinary pathogens (1), make Sindbis virus infection of neonatal mice an appropriate system for the study of viral pathogenesis.One approach to an understanding of the complex process of pathogenesis is to begin with a specific and quantifiable phenotype related to disease. We have taken this approach in a study of viral virulence, using the measurable properties of percent mortality and mean survival time of neonatal ICR-L+ mice injected subcutaneously with Sindbis virus. Wild-type, virulent Sindbis virus infection of newborn mice by this route leads to 100% mortality and a mean survival time of 4-6 days. Mutant strains of Sindbis virus, developed by serial passage in baby hamster kidney (BHK) cells under stringent pressure for rapid growth, show reduced, or attenuated, virulence; mortality is always less than 100% and the mean survival time is 12-14 days (5). Comparison of attenuated and virulent viruses isolated during the passage series showed that attenuation in vivo was consistently correlated with accelerated penetration of BHK cells. Virulent revertants of the attenuated prototype strain SB-RL also reverted with respect to penetration rate. Rapid penetration was, thereby, identified as an in vitro marker for attenuation, and a mutant selected directly for accelerated penetration was attenuated (5). A second in vitro marker for attenuation was identified in studies with monoclonal antibodies raised to the attenuated SB-RL virus. Two of these antibodies, R6 and R13, which define epitopes on the E2 glycoprotein, preferentially neutralized the attenuated, fast-penetrating strains (5). A mutant of SB-RL selected for resistance to neut...

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Section: Resultsmentioning

confidence: 99%

A single nucleotide change in the E2 glycoprotein gene of Sindbis virus affects penetration rate in cell culture and virulence in neonatal mice.

Davis¹,

Fuller²,

Dougherty³

et al. 1986

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

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“…-The avirulent virus fails to multiply (or multiplies only at a low rate) in the "target" tissue manifesting the virulence. For example, replication in the central nervous system (CNS) is the basis of virulence for many viruses, and attenuation arises from a reduced ability to replicate in the CNS but replication is nearly normal in other tissues (Venezuelan equine encephalitis virus: Krieger et al 1979;Emini and Wiebe 1981;reovirus: Kaye et al 1986;herpes simplex virus: Javier et al 1987).…”

Section: Iic Tissue Tropismsmentioning

confidence: 99%

Perspective: Virulence

Bull¹

1994

Evolution

387

277

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Why do parasites harm their hosts? Intuition suggests that parasites should evolve to be benign whenever the host is needed for transmission. Yet a growing theoretical literature offers several models to explain why natural selection may favor virulent parasites over avirulent ones. This perspective first organizes these models into a simple framework and then evaluates the empirical evidence for and against the models. There is relatively scant evidence to support any of the models rigorously, and indeed, there are only a few unequivocal observations of virulence actually evolving in parasite populations. These shortcomings are surmountable, however, and empirical models of host-parasite interactions have been developed for many kinds of pathogens so that the relevant data could be acquired in the near future.

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Section: Iic Tissue Tropismsmentioning

confidence: 99%

Virulence

1994

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Abstract. -Why do parasites harm their hosts? Intuition suggests that parasites should evolve to be benign whenever the host is needed for transmission. Yet a growing theoretical literature offers several models to explain why natural selection may favor virulent parasites over avirulent ones. This perspective first organizes these models into a simple framework and then evaluates the empirical evidence for and against the models. There is relatively scant evidence to support any of the models rigorously, and indeed, there are only a few unequivocal observations of virulence actually evolving in parasite populations. These shortcomings are surmountable, however, and empirical models of host-parasite interactions have been developed for many kinds of pathogens so that the relevant data could be acquired in the near future.Aside from academic interest, the evolution of virulence has potential medical and agricultural ramifications that may provide evolutionary biology with opportunities for contributions to human welfare. For example, understanding the evolution of parasite virulence may help us design better vaccines, prevent the emergence of highly virulent strains in the future, and diminish the virulence of present pathogens. These potential applications notwithstanding, the usefulness of an evolutionary theory of virulence to social problems has not been demonstrated and is even doubtful in some cases. One promising area for contributions from evolutionary theory is in designing live, attenuated vaccines.Key words.-Evolution, microparasite, population biology, virulence, virus.Received April 10, 1994. Accepted April 12, 1994 Evolutionary biologists are becoming increasingly enamored of the idea that evolutionary thinking may contribute substantially to the alleviation of human health problems. Much of the fanfare has centered on applications of natural selection to disease (the Darwinian Medicine school; Profet 1991Profet , 1993Williams and Nesse 1991; Ewald 1994) but these applications of evolutionary biology are so far without obvious success in penetrating the fields of medicine. In contrast, a far more visible impact from evolutionary biology is the use of phylogenetic reconstruction to trace routes and sources of in-I

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An attenuated mutant of Venezuelan encephalitis virus: Biochemical alterations and their genetic association with attenuation

Cited by 13 publications

References 30 publications

A single nucleotide change in the E2 glycoprotein gene of Sindbis virus affects penetration rate in cell culture and virulence in neonatal mice.

A single nucleotide change in the E2 glycoprotein gene of Sindbis virus affects penetration rate in cell culture and virulence in neonatal mice.

Perspective: Virulence

Virulence

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