The nsP3 macro domain is important for Sindbis virus replication in neurons and neurovirulence in mice

• Published in: Virology (New York, N.Y.) Vol. 388; no. 2; pp. 305 - 314
• Main Authors: Park, Eunhye, Griffin, Diane E
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.06.2009
• Subjects: Alphavirus; Animals; Binding Sites - genetics; Cell Line; Encephalitis; Encephalomyelitis - genetics; Encephalomyelitis - physiopathology; Encephalomyelitis - virology; Infectious Disease; Mice; Mutation; Neurons; Neurons - metabolism; Neurons - virology; Poly Adenosine Diphosphate Ribose - genetics; Poly(ADP-ribose); Protein Structure, Tertiary - genetics; Rats; Sindbis virus; Sindbis Virus - genetics; Sindbis Virus - pathogenicity; Sindbis Virus - physiology; Structure-Activity Relationship; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virulence - genetics; Virus Replication - genetics; Virus Replication - physiology; Encephalitis; Alphavirus; Mice; Neurons; Poly(ADP-ribose)
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2009.03.031

Abstract Sindbis virus (SINV), the prototype alphavirus, contains a macro domain in the highly conserved N-terminal region of nonstructural protein 3 (nsP3). However, the biological role of the macro domain is unclear. Mutations of amino acids 10 and 24 from asparagine to alanine in the ADP-ribose binding region of the macro domain impaired SINV replication and viral RNA synthesis particularly in neurons, but did not alter binding of poly(ADP-ribose). Mutation at position 10 had the greatest effect and caused nsP3 instability in neurons, decreased SINV-induced death of mature, but not immature neurons, and attenuated virulence in 2 week-old, but not 5 day-old mice. A compensatory mutation at amino acid 31 in the macro domain of nsP3, as well as reversion of mutated amino acid 10, occurred during replication of double mutant SINV in vitro and in vivo. The nsP3 macro domain is important for SINV replication and age-dependent susceptibility to encephalomyelitis.