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Short Duration of Elevated vIRF-1 Expression during Lytic Replication of Human Herpesvirus 8 Limits Its Ability To Block Antiviral Responses Induced by Alpha Interferon in BCBL-1 Cells

Veronika P. Pozharskaya,¹ Laura L. Weakland,^1, James C. Zimring,^1,2 Laurie T. Krug,¹ Elizabeth R. Unger,³ Andrew Neisch,² Harish Joshi,⁴ Naoki Inoue,^3, and Margaret K. Offermann^1*

Winship Cancer Institute,¹ Department of Pathology,² Department of Cell Biology, Emory University, Atlanta, Georgia 30322,⁴ Centers for Disease Control and Prevention, Atlanta, Georgia 30333³

Received 3 November 2003/ Accepted 6 February 2004

Human herpesvirus 8 (HHV-8) encodes multiple proteins that disrupt the host antiviral response, including viral interferon (IFN) regulatory factor 1 (vIRF-1). The product of the vIRF-1 gene blocks responses to IFN when overexpressed by transfection, but the functional consequence of vIRF-1 that is expressed during infection with HHV-8 is not known. These studies demonstrate that BCBL-1 cells that were latently infected with HHV-8 expressed low levels of vIRF-1 that were associated with PML bodies, whereas much higher levels of vIRF-1 were transiently expressed during the lytic phase of HHV-8 replication. The low levels of vIRF-1 that were associated with PML bodies were insufficient to block alpha IFN (IFN-)-induced alterations in gene expression, whereas cells that expressed high levels of vIRF-1 were resistant to some changes induced by IFN-, including the expression of the double-stranded-RNA-activated protein kinase. High levels of vIRF-1 were expressed for only a short period during the lytic cascade, so many cells with HHV-8 in the lytic phase responded to IFN- with increased expression of antiviral genes and enhanced apoptosis. Furthermore, the production of infectious virus was severely compromised when IFN- was present early during the lytic cascade. These studies indicate that the transient expression of high levels of vIRF-1 is inadequate to subvert many of the antiviral effects of IFN- so that IFN- can effectively induce apoptosis and block production of infectious virus when present early in the lytic cascade of HHV-8.

Present address: Georgia Cancer Specialists, Atlanta, Ga.

Present address: Department of Virology I, National Institute of Infectious Disease, Tokyo, Japan.

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