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Journal of Virology, May 2002, p. 4430-4440, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4430-4440.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cell Cycle Status Affects Coxsackievirus Replication, Persistence, and Reactivation In Vitro{dagger}

Ralph Feuer, Ignacio Mena,,{ddagger} Robb Pagarigan, Mark K. Slifka,,§ and J. Lindsay Whitton*

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Received 4 September 2001/ Accepted 29 January 2002

Enteroviral persistence has been implicated in the pathogenesis of several chronic human diseases, including dilated cardiomyopathy, insulin-dependent diabetes mellitus, and chronic inflammatory myopathy. However, these viruses are considered highly cytolytic, and it is unclear what mechanisms might permit their long-term survival. Here, we describe the generation of a recombinant coxsackievirus B3 (CVB3) expressing the enhanced green fluorescent protein (eGFP), which we used to mark and track infected cells in vitro. Following exposure of quiescent tissue culture cells to either wild-type CVB3 or eGFP-CVB3, virus production was very limited but increased dramatically after cells were permitted to divide. Studies with cell cycle inhibitors revealed that cells arrested at the G1 or G1/S phase could express high levels of viral polyprotein and produced abundant infectious virus. In contrast, both protein expression and virus yield were markedly reduced in quiescent cells (i.e., cells in G0) and in cells blocked at the G2/M phase. Following infection with eGFP-CVB3, quiescent cells retained viral RNA for several days in the absence of infectious virus production. Furthermore, RNA extracted from nonproductive quiescent cells was infectious when transfected into dividing cells, indicating that CVB3 appears to be capable of establishing a latent infection in G0 cells, at least in tissue culture. Finally, wounding of infected quiescent cells resulted in viral protein expression limited to cells in and adjacent to the lesion. We suggest that (i) cell cycle status determines the distribution of CVB3 during acute infection and (ii) the persistence of CVB3 in vivo may rely on infection of quiescent (G0) cells incapable of supporting viral replication; a subsequent change in the cell cycle status may lead to virus reactivation, triggering chronic viral and/or immune-mediated pathology in the host.

* Corresponding author. Mailing address: Dept. of Neuropharmacology, CVN-9, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: 858-784-7090. Fax: 858-784-7380. E-mail: lwhitton{at}scripps.edu.

{dagger} This is manuscript number 14295-NP from the Scripps Research Institute.

{ddagger} Present address: Institut Pasteur, Paris, France.

§ Present address: Oregon Health Sciences University, Portland, Oreg.

Journal of Virology, May 2002, p. 4430-4440, Vol. 76, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.9.4430-4440.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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Copyright © 2002 by the American Society for Microbiology. All rights reserved.