Host translation shutoff mediated by non-structural protein 2 is a critical factor in the antiviral state resistance of Venezuelan equine encephalitis virus.
Most previous studies of interferon-alpha/beta (IFN-α/β) response antagonism by alphaviruses have focused upon interruption of IFN-α/β induction and/or receptor signaling cascades. Infection of mice with Venezuelan equine encephalitis alphavirus (VEEV) or Sindbis virus (SINV) induces serum IFN-α/β, that elicits a systemic antiviral state in uninfected cells successfully controlling SINV but not VEEV replication. Furthermore, VEEV replication is more resistant than that of SINV to a pre-existing antiviral state in vitro. While host macromolecular shutoff is proposed as a major antagonist of IFN-α/β induction, the underlying mechanisms of alphavirus resistance to a pre-existing antiviral state are not fully defined, nor is the mechanism for the greater resistance of VEEV. Here, we have separated viral transcription and translation shutoff with multiple alphaviruses, identified the viral proteins that induce each activity, and demonstrated that VEEV nonstructural protein 2-induced translation shutoff is likely a critical factor in enhanced antiviral state resistance of this alphavirus.
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.
Nishank
N
Bhalla
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.
Chengqun
C
Sun
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.
L K
LK
Metthew Lam
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.
Christina L
CL
Gardner
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.
Kate D
KD
Ryman
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address: Klimstra@pitt.edu.
William B
WB
Klimstra
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D060467:Disease Resistance; D004666:Encephalitis Virus, Venezuelan Equine / Q000187:drug effects / Q000502:physiology*; D004685:Encephalomyelitis, Venezuelan Equine / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000821:virology*; D006736:Horses; D054884:Host-Pathogen Interactions; D006801:Humans; D007372:Interferons / Q000096:biosynthesis / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D010641:Phenotype; D014176:Protein Biosynthesis; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
D000998:Antiviral Agents; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D007372:Interferons
Alphavirus; Antiviral state resistance; Chikungunya virus; Eastern equine encephalitis virus; Interferon; Nonstructural protein 2; Sindbis virus; Transcription shutoff; Translation shutoff; Venezuelan equine encephalitis virus