Alpha/beta interferons regulate murine gammaherpesvirus latent gene expression and reactivation from latency.
Alpha/beta interferon (IFN-alpha/beta) protects the host from virus infection by inhibition of lytic virus replication in infected cells and modulation of the antiviral cell-mediated immune response. To determine whether IFN-alpha/beta also modulates the virus-host interaction during latent virus infection, we infected mice lacking the IFN-alpha/beta receptor (IFN-alpha/betaR(-/-)) and wild-type (wt; 129S2/SvPas) mice with murine gammaherpesvirus 68 (gammaHV68), a lymphotropic gamma-2-herpesvirus that establishes latent infection in B cells, macrophages, and dendritic cells. IFN-alpha/betaR(-/-) mice cleared low-dose intranasal gammaHV68 infection with wt kinetics and harbored essentially wt frequencies of latently infected cells in both peritoneum and spleen by 28 days postinfection. However, latent virus in peritoneal cells and splenocytes from IFN-alpha/betaR(-/-) mice reactivated ex vivo with >40-fold- and 5-fold-enhanced efficiency, respectively, compared to wt cells. Depletion of IFN-alpha/beta from wt mice during viral latency also significantly increased viral reactivation, demonstrating an antiviral function of IFN-alpha/beta during latency. Viral reactivation efficiency was temporally regulated in both wt and IFN-alpha/betaR(-/-) mice. The mechanism of IFN-alpha/betaR action was distinct from that of IFN-gammaR, since IFN-alpha/betaR(-/-) mice did not display persistent virus replication in vivo. Analysis of viral latent gene expression in vivo demonstrated specific upregulation of the latency-associated gene M2, which is required for efficient reactivation from latency, in IFN-alpha/betaR(-/-) splenocytes. These data demonstrate that an IFN-alpha/beta-induced pathway regulates gammaHV68 gene expression patterns during latent viral infection in vivo and that IFN-alpha/beta plays a critical role in inhibiting viral reactivation during latency.
Barton
Erik S
ES
Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA.
Lutzke
Mary L
ML
Rochford
Rosemary
R
Virgin
Herbert W
HW
D000818:Animals; D018142:Gammaherpesvirinae / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006566:Herpesviridae Infections / Q000276:immunology; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D008099:Liver / Q000276:immunology / Q000821:virology; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics*; D013154:Spleen / Q000276:immunology / Q000821:virology*; D017735:Virus Latency / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication
D016898:Interferon-alpha; D017471:Receptors, Interferon; D016899:Interferon-beta