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Journal of Virology, April 2005, p. 5227-5231, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.5227-5231.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Ex Vivo Stimulation of B Cells Latently Infected with Gammaherpesvirus 68 Triggers Reactivation from Latency

Janice M. Moser,1 Jason W. Upton,1,2 Kathleen S. Gray,1 and Samuel H. Speck1*

Center for Emerging Infectious Diseases, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia,1 Graduate Program in Molecular Cell Biology, Washington University School of Medicine, St. Louis, Missouri2

Received 10 September 2004/ Accepted 23 November 2004

Murine gammaherpesvirus 68 ({gamma}HV68) infection of mice results in the establishment of a chronic infection, which is largely maintained through latent infection of B lymphocytes. Acute virus replication is almost entirely cleared by 2 weeks postinfection. Spontaneous reactivation of {gamma}HV68 from latently infected splenocytes upon ex vivo culture can readily be detected at the early stages of infection (e.g., day 16). However, by 6 weeks postinfection, very little spontaneous reactivation is detected upon explant into tissue culture. Here we report that stimulation of latently infected splenic B cells harvested at late times postinfection with cross-linking surface immunoglobulin (Ig), in conjunction with anti-CD40 antibody treatment, triggers virus reactivation. As expected, this treatment resulted in B-cell activation, as assessed by upregulation of CD69 on B cells, and ultimately B-cell proliferation. Since anti-Ig/anti-CD40 stimulation resulted in splenic B-cell proliferation, we assessed whether this reactivation stimulus could overcome the previously characterized defect in virus reactivation of a v-cyclin null {gamma}HV68 mutant. This analysis demonstrated that anti-Ig/anti-CD40 stimulation could drive reactivation of the v-cyclin null mutant virus in latently infected splenocytes, but not to the levels observed with wild-type {gamma}HV68. Thus, there appears to be a role for the v-cyclin in B cells following anti-Ig/anti-CD40 stimulation independent of the induction of the cell cycle. Finally, to assess signals that are not mediated through the B-cell receptor, we demonstrate that addition of lipopolysaccharide to explanted splenocyte cultures also enhanced virus reactivation. These studies complement and extend previous analyses of Epstein-Barr virus and Kaposi's sarcoma-associated virus reactivation from latently infected cell lines by investigating reactivation of {gamma}HV68 from latently infected primary B cells recovered from infected hosts.

* Corresponding author. Mailing address: Center for Emerging Infectious Diseases, Yerkes National Primate Research Center, Emory University School of Medicine, 954 Gatewood Rd., NE, Atlanta, GA 30329. Phone: (404) 727-7665. Fax: (404) 727-7768. E-mail: sspeck{at}rmy.emory.edu.

Journal of Virology, April 2005, p. 5227-5231, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.5227-5231.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gargano, L. M., Forrest, J. C., Speck, S. H. (2009). Signaling through Toll-Like Receptors Induces Murine Gammaherpesvirus 68 Reactivation In Vivo. J. Virol. 83: 1474-1482 [Abstract] [Full Text]  
  • Forrest, J. C., Speck, S. H. (2008). Establishment of B-Cell Lines Latently Infected with Reactivation-Competent Murine Gammaherpesvirus 68 Provides Evidence for Viral Alteration of a DNA Damage-Signaling Cascade. J. Virol. 82: 7688-7699 [Abstract] [Full Text]  
  • Upton, J. W., Speck, S. H. (2006). Evidence for CDK-Dependent and CDK-Independent Functions of the Murine Gammaherpesvirus 68 v-Cyclin. J. Virol. 80: 11946-11959 [Abstract] [Full Text]  
  • Moser, J. M., Upton, J. W., Allen, R. D. III, Wilson, C. B., Speck, S. H. (2005). Role of B-Cell Proliferation in the Establishment of Gammaherpesvirus Latency. J. Virol. 79: 9480-9491 [Abstract] [Full Text]  


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