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/beta R-/-) and wild-type (wt; 129S2/SvPas) mice with murine gammaherpesvirus 68 (gamma HV68), a lymphotropic gamma-2-herpesvirus that establishes latent infection in B cells, macrophages, and dendritic cells. 1FN-alpha/beta R-/- mice cleared low-dose intranasal gamma HV68 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/beta R-/- 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/beta R(-/-)mice. The mechanism of IFN-alpha/beta R action was distinct from that of IFN-gamma R, since IFN-alpha/beta R-/- 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/beta R-/- splenocytes. These data demonstrate that an IFN-alpha/beta-induced pathway regulates gamma HV68 gene expression patterns during latent viral infection in vivo and that IFN-alpha/beta plays a critical role in inhibiting viral reactivation during latency.
机构:
Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Dunn, GP
;
Bruce, AT
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Bruce, AT
;
Sheehan, KCF
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Sheehan, KCF
;
Shankaran, V
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Shankaran, V
;
Uppaluri, R
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Uppaluri, R
;
Bui, JD
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Bui, JD
;
Diamond, MS
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Diamond, MS
;
Koebel, CM
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Koebel, CM
;
Arthur, C
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Arthur, C
;
White, JM
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
White, JM
;
Schreiber, RD
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Dunn, GP
;
Bruce, AT
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Bruce, AT
;
Sheehan, KCF
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Sheehan, KCF
;
Shankaran, V
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Shankaran, V
;
Uppaluri, R
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Uppaluri, R
;
Bui, JD
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Bui, JD
;
Diamond, MS
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Diamond, MS
;
Koebel, CM
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Koebel, CM
;
Arthur, C
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
Arthur, C
;
White, JM
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA
White, JM
;
Schreiber, RD
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Washington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USAWashington Univ, Sch Med, Ctr Immunol, Dept Pathol & Immunol, St Louis, MO 63110 USA