Abstract
Virus infection of a cell generally evokes an immune response by the host to defeat the intruder in its effort. Many viruses have developed an array of strategies to evade or antagonize host antiviral responses. Kaposi's sarcoma-associated herpesvirus (KSHV) is demonstrated in this report to be able to prevent activation of host antiviral defense mechanisms upon infection. Cells infected with wild-type KSHV were permissive for superinfection with vesicular stomatitis virus (VSV), suggesting that KSHV virions fail to induce host antiviral responses. We previously showed that ORF45, a KSHV immediate-early protein as well as a tegument protein of virions, interacts with IRF-7 and inhibits virus-mediated type I interferon induction by blocking IRF-7 phosphorylation and nuclear translocation (Zhu et al., Proc. Natl. Acad. Sci. USA. 99:5573-5578, 2002). Here, using an ORF45-null recombinant virus, we demonstrate a profound role of ORF45 in inhibiting host antiviral responses. Infection of cells with an ORF45-null mutant recombinant KSHV (BAC-stop45) triggered an immune response that resisted VSV super-infection, concomitantly associated with appreciable increases in transcription of type I IFN and downstream anti-viral effector genes. Gain-of-function analysis showed that ectopic expression of ORF45 in human fibroblast cells by a lentivirus vector decreased the antiviral responses of the cells. shRNA-mediated silencing of IRF-7, that predominantly regulates both the early and late phase induction of type I IFNs, clearly indicated its critical contribution to the innate antiviral responses generated against incoming KSHV particles. Thus ORF45 through its targeting of the crucial IRF-7 regulated type I IFN antiviral responses significantly contributes to the KSHV survival immediately following a primary infection allowing for progression onto subsequent stages in its life-cycle.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8 (HHV-8), is a human DNA tumor virus belonging to the gamma herpesviridae family [1,2]
Viral infection and ongoing lytic replication are generally under host antiviral surveillance. These viral events induce specific antiviral immune responses by the host cell constituted by the synthesis of type I IFNs (IFN-a/b) that activates the transcription of a group of downstream IFN-stimulated genes (ISGs) that encode antiviral IFN effector proteins [15]
Human foreskin fibroblast (HFF) cells were infected with 5 genome copies per cell of intact or UV-inactivated KSHV and at 16 hours postinfection were superinfected with approximately 100 plaque forming units (Pfu) of vesicular stomatitis virus (VSV)
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8 (HHV-8), is a human DNA tumor virus belonging to the gamma herpesviridae family [1,2]. The host cell responds to these events through the creation of an antiviral state, predominantly associated with the synthesis and secretion of soluble type I interferon (IFN-a/b), that make up vital components of the host innate immune system [5,6]. This is exemplified in related herpesviruses, like herpes simplex virus (HSV) and human cytomegalovirus (HCMV), wherein the binding of the respective envelope glycoproteins, gD and gB, to the cell surface receptors, trigger the host cell antiviral responses through type I IFN signaling [7,8]. In KSHV the initial interaction of the viral glycoprotein gpK8.1 with cell surface components was shown to trigger the type I IFN pathway [9]
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