title: A substitution in nsP1 combined with a double substitution in E2 glycoprotein renders Sindbis-like virus XJ-160 fully neurovirulent for adult mice.
abstract: Sindbis virus (SV) can be rendered neurovirulent for adult mice by a double substitution within the E2 glycoprotein, including replacing Gln at position 55 of E2 with a His (E2-55: Gln-His) and E2-70: Glu to Lys. However, the mutant Sindbis-like virus XJ-160 with the double substitution (BR-E5570) does not show neurovirulence for adult mice, although the mutant apparently reduced the average survival time of neonatal mice. To produce an XJ-160 virus neurovirulent for adult mice, the BR-E5570 virus containing the double substitution was provided with another substitution in the nsP1 region (nsP1-173: Thr-Ile), which could enhance viral infectivity and neurovirulence for neonatal mice. The mutant containing these three substitutions was accordingly designated as BR-5570-ns173. Like the BR-XJ160 virus derived from the wild-type clone, BR-E5570 and BR-E5570-ns173 were both virulent for newborn mice, between which BR-E5570-ns173 virus showed the greatest neurovirulence. Furthermore, only BR-E5570-ns173 virus was fully neurovirulent for 14-day-old mice, and this fatal adult mouse-virulence was dependent on the E2 double substitutions at positions 55 and 70. Compared with BR-XJ160, both the mutants showed a higher capacity for propagation both in cultured cells and in the mouse brain. In particular, BR-E5570-ns173 virus showed a more persistent existence and higher titer in the brains of 7-day-old mice. These findings indicate that the substitution at nsP1-173 combination with a double substitution in the E2 region renders the XJ-160 virus fully neurovirulent for adult mice, and this neurovirulence may be related to the increased efficiency and persistence of propagation of this virus.
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Viral Disease Control and Prevention, Beijing, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China. Electronic address: zhuwuyang1971@sohu.com.
authors.forename: Wuyang
authors.initials: W
authors.lastname: Zhu
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Viral Disease Control and Prevention, Beijing, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Deng
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Viral Disease Control and Prevention, Beijing, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Viral Disease Control and Prevention, Beijing, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
authors.forename: Huanqin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Yunnan Tropical and Subtropical Animal Virus Diseases Laboratory, Yunnan Animal Science and Veterinary Institute, Kunming, Yunnan, People's Republic of China.
authors.forename: Jinglin
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Viral Disease Control and Prevention, Beijing, People's Republic of China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People's Republic of China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Liang
mesh_terms: D018354:Alphavirus Infections / Q000401:mortality / Q000821:virology*; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D051379:Mice; D009422:Nervous System Diseases / Q000401:mortality / Q000821:virology*; D012845:Sindbis Virus / Q000472:pathogenicity / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D014774:Virulence / Q000235:genetics
chemical_list: D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; C064950:glycoprotein E2, Sindbis virus
keywords: Neurovirulence; Sindbis-like virus XJ-160; Substitution