Attenuation of Chikungunya virus vaccine strain 181/clone 25 is determined by two amino acid substitutions in the E2 envelope glycoprotein
Autor(es): Gorchakov Rodion, Wang Eryu, Leal Grace, Forrester Naomi L, Plante Kenneth, Rossi Shannan L, Partidos Charalambos D, Adams A Paige, Seymour Robert L, Weger James, Borland Erin M, Sherman Michael B, Powers Ann M, Osorio Jorge E, Weaver Scott C
Resumo: Chikungunya virus (CHIKV) is the mosquito-borne alphavirus that is the etiologic agent of massive outbreaks of arthralgic febrile illness that recently affected millions of people in Africa - Asia. The only CHIKV vaccine that has been tested in humans, strain 181/clone 25, is a live-attenuated derivative of Southeast Asian human isolate strain AF15561. The vaccine was immunogenic in phase I - II clinical trials; however, it induced transient arthralgia in 8% of the vaccinees. There are five amino acid differences between the vaccine - its parent, as well as five synonymous mutations, none of which involves cis-acting genome regions known to be responsible for replication or packaging. To identify the determinants of attenuation, we therefore tested the five nonsynonymous mutations by cloning them individually or in different combinations into infectious clones derived from two wild-type (WT) CHIKV strains, La Reunion - AF15561. Levels of virulence were compared with those of the WT strains - the vaccine strain in two different murine models: infant CD1 - adult A129 mice. An attenuated phenotype indistinguishable from that of the 181/clone 25 vaccine strain was obtained by the simultaneous expression of two E2 glycoprotein substitutions, with intermediate levels of attenuation obtained with the single E2 mutations. The other three amino acid mutations, in nsP1, 6K, - E1, did not have a detectable effect on CHIKV virulence. These results indicate that the attenuation of strain 181/clone 25 is mediated by two point mutations, explaining the phenotypic instability observed in human vaccinees - also in our studies.
Imprenta: Journal of Virology, v. 86, n. 11, p. 6084-6096, 2012
Identificador do objeto digital: 10.1128/JVI.06449-11
Descritores: Chikungunya virus - Cytopathology ; Chikungunya virus - Genome ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Immunology
Data de publicação: 2012
