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Journal of Virology, January 2006, p. 360-371, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.360-371.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role for nsP2 Proteins in the Cessation of Alphavirus Minus-Strand Synthesis by Host Cells

Dorothea L. Sawicki,1* Silvia Perri,2 John M. Polo,2 and Stanley G. Sawicki1

Microbiology and Immunology Department, Medical University of Ohio, Toledo, Ohio 43614,1 Chiron Corporation, Emeryville, California2

Received 29 March 2005/ Accepted 22 September 2005

In order to establish nonlytic persistent infections (PI) of BHK cells, replicons derived from Sindbis (SIN) and Semliki Forest (SFV) viruses have mutations in nsP2. Five different nsP2 PI replicons were compared to wild-type (wt) SIN, SFV, and wt nsPs SIN replicons. Replicon PI BHK21 cells had viral RNA synthesis rates that were less than 5% of those of the wt virus and ~10% or less of those of SIN wt replicon-infected cells, and, in contrast to wt virus and replicons containing wt nsP2, all showed a phenotype of continuous minus-strand synthesis and of unstable, mature replication/transcription complexes (RC+) that are active in plus-strand synthesis. Minus-strand synthesis and incorporation of [3H]uridine into replicative intermediates differed among PI replicons, depending on the location of the mutation in nsP2. Minus-strand synthesis by PI cells appeared normal; it was dependent on continuous P123 and P1234 polyprotein synthesis and ceased when protein synthesis was inhibited. The failure by the PI replicons to shut off minus-strand synthesis was not due to some defect in the PI cells but rather was due to the loss of some function in the mutated nsP2. This was demonstrated by showing that superinfection of PI cells with wt SFV triggered the shutdown of minus-strand synthesis, which we believe is a host response to infection with alphaviruses. Together, the results indicate alphavirus nsP2 functions to engage the host response to infection and activate a switch from the early-to-late phase. The loss of this function leads to continuous viral minus-strand synthesis and the production of unstable RC+.

* Corresponding author. Mailing address: Medical University of Ohio, Department of Microbiology and Immunology, 3055 Arlington Avenue, Toledo, OH 43614. Phone: (419) 383-4337. Fax: (419) 383-3002. E-mail: dsawicki{at}meduohio.edu.

Journal of Virology, January 2006, p. 360-371, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.360-371.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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