title: 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.
abstract: 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-alpha)-induced alterations in gene expression, whereas cells that expressed high levels of vIRF-1 were resistant to some changes induced by IFN-alpha, 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-alpha with increased expression of antiviral genes and enhanced apoptosis. Furthermore, the production of infectious virus was severely compromised when IFN-alpha 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-alpha so that IFN-alpha can effectively induce apoptosis and block production of infectious virus when present early in the lytic cascade of HHV-8.
authors.affiliation: Winship Cancer Institute, Emory University, 1365-B Clifton Road N.E., Atlanta, GA 30322, USA.
authors.forename: Veronika P
authors.initials: VP
authors.lastname: Pozharskaya
authors.forename: Laura L
authors.initials: LL
authors.lastname: Weakland
authors.forename: James C
authors.initials: JC
authors.lastname: Zimring
authors.forename: Laurie T
authors.initials: LT
authors.lastname: Krug
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Unger
authors.forename: Andrew
authors.initials: A
authors.lastname: Neisch
authors.forename: Harish
authors.initials: H
authors.lastname: Joshi
authors.forename: Naoki
authors.initials: N
authors.lastname: Inoue
authors.forename: Margaret K
authors.initials: MK
authors.lastname: Offermann
mesh_terms: D001402:B-Lymphocytes; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha / Q000276:immunology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D014764:Viral Proteins; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D014157:Transcription Factors; D014764:Viral Proteins; C413486:viral interferon regulatory factors