Human cytomegalovirus UL83-coded pp65 virion protein inhibits antiviral gene expression in infected cells

Abstract

The initial interaction of human cytomegalovirus with fibroblasts triggers, and then partially blocks, an innate immune response pathway that leads to the induction of IFN-responsive genes and proinflammatory chemokines. Infection of fibroblasts with human cytomegalovirus inhibited their ability to respond to exogenous IFN. Consistent with the observation that the block did not depend on de novo viral protein synthesis, ectopic expression of the viral UL83-coded pp65, an abundant virion protein, inhibited IFN signaling. Furthermore, DNA array analysis showed that infection with a pp65-deficient mutant virus caused a much stronger induction of many IFN-response and proinflammatory chemokine RNAs than infection with wild-type virus. The nuclear DNA-binding activities of transcription factors NF-B and IRF1 were induced to a much greater extent after infection with the pp65-deficient mutant than with wild-type virus. IFN-stimulated gene factor 3 DNA-binding was modestly enhanced, whereas IRF3 activity was not affected by mutation of pp65. Together, these results imply that pp65, which is delivered to newly infected cells in the virion, antagonizes a pathway that affects NF-B and IRF1 and prevents the accumulation of mRNAs encoded by numerous cellular antiviral genes.

Mouse cytomegalovirus inhibits beta interferon (IFN-β) gene expression and controls activation pathways of the IFN-β enhanceosome

“…4) and downregulates the basal NF-kB activity. The HCMV tegument protein pp65 (pUL83) was reported to counteract innate antiviral defence, including NF-kB activity (Browne & Shenk, 2003) and IRF3 activation (Abate et al, 2004). In addition, an indirect effect on inhibition of IFN-b expression by deletion of the UL83-ORF was described previously (Taylor & Bresnahan, 2006b) DCs respond to MCMV with a strong type I IFN production (Krug et al, 2004;Tabeta et al, 2004;Delale et al, 2005;Andoniou et al, 2005).…”

“…protein kinase R and RNaseL (Child et al, 2004(Child et al, , 2006Valchanova et al, 2006). A HCMV mutant lacking UL83 was found to be deficient in inhibition of IFNb gene expression, leading to the conclusions that pUL83/ pp65 interferes with IRF3-or NF-kB-mediated gene induction (Browne & Shenk, 2003;Abate et al, 2004). Moreover, the HCMV IE2 protein pp86 was identified as blocking IFN-b gene induction by inhibiting NF-kB DNA binding (Taylor & Bresnahan, 2006a).…”

RICK Activates a NF-κB-dependent Anti-human Cytomegalovirus Response

“…We conclude that an essential component of the inhibitory supernatant generated by RICK expression plus HCMV infection is IFN-␤. It has been demonstrated clearly that HCMV can interfere with the viral-induced interferon synthesis (54,55,56). Indeed, the interferon response to UVinactivated HCMV infection is robust, whereas during the course of active HCMV replication, this response is largely suppressed (55,56).…”

“…It has been demonstrated clearly that HCMV can interfere with the viral-induced interferon synthesis (54,55,56). Indeed, the interferon response to UVinactivated HCMV infection is robust, whereas during the course of active HCMV replication, this response is largely suppressed (55,56). To test whether RICK is able to override these mechanisms of HCMV interferon suppression, we analyzed IFN-␤ induction in the presence of very high m.o.i.…”

Differential Regulation of NF-κB Signaling during Human Cytomegalovirus Infection

“…Although a viral function in downregulating NF-κB signaling at the early stage of infection has been found, it is believed that the The mechanism by which pp65 inhibits the production of IFNs is controversial. One study demonstrated that pp65 inhibits IRF1 and NF-κB activity (23), while another study suggested that pp65 inhibits IRF3 activation (24). It is likely that tegument pp65 rapidly moves to the nucleus after it is delivered to infected cells and suppresses excessive antiviral cellular gene expression at very early times after infection.…”