Lack of nsP2-specific nuclear functions attenuates chikungunya virus replication both in vitro and in vivo.
Chikungunya virus (CHIKV) is an important arthritogenic human pathogen that is already circulating in both hemispheres. In the present study, we substituted VLoop, located on the surface of nsP2, by other amino acid sequences. These modifications had deleterious effects on viral nuclear functions and made CHIKV incapable of interfering with the induction of type I interferon and the antiviral response in both mouse and human cells. Importantly, the identified mutations have no significant effects on the synthesis of virus-specific RNAs and viral structural proteins. The designed mutants induced a few orders of magnitude lower viremia but remained highly immunogenic in mice. Thus, the proposed modifications of nsP2 can additionally improve the safety of the attenuated strain CHIKV 181/25. Furthermore, defined mutations in the macro domain of another nonstructural protein, nsP3, additionally reduce cytopathogenicity of nsP2 mutants in human cells, and can be potentially applied for CHIKV attenuation.
['Meshram|Chetan D|CD|', 'Lukash|Tetyana|T|', 'Phillips|Aaron T|AT|', 'Akhrymuk|Ivan|I|', 'Frolova|Elena I|EI|', 'Frolov|Ilya|I|']
D000818:Animals D002460:Cell Line D002467:Cell Nucleus D065632:Chikungunya Fever D002646:Chikungunya virus D006801:Humans D007370:Interferon Type I D051379:Mice D008810:Mice, Inbred C57BL D009154:Mutation D000072417:Protein Domains D012367:RNA, Viral D017361:Viral Nonstructural Proteins D014779:Virus Replication
Chikungunya virus nsP2 nsP3 Alphaviruses Cytopathic effect Transcription inhibition Vaccines Viral RNA replication Virus-host interaction