Herpes Simplex Virus Type 1 Induction of Persistent NF-κB Nuclear Translocation Increases the Efficiency of Virus Replication

Abstract

The latent form of the dimeric transcription factor NF-kappa B is sequestered in the cytoplasm by proteins containing ankyrin repeats, such as 1 kappa B alpha and beta, or by the p105 precursor form of the NF-kappa B p50 subunit. Tumor necrosis factor alpha or virus infection can cause targeted destruction of 1 kappa B and nuclear translocation of NF-kappa B. Following translocation, NF-kappa B mediates immune, inflammatory, or anti-apoptotic responses. Here we present evidence that beginning at around 6 h postinfection, herpes simplex virus (HSV) induces a persistent translocation of NF-kappa B into the nucleus of C33 cells, coincident with loss of both 1 kappa B alpha and 1 kappa B beta. Translocation failed to occur when infecting virus was preincubated with neutralizing antibody to viral envelope glycoproteins gD or gH, thus preventing entry, or when cells infected with viruses expressing mutated forms of immediate-early regulatory proteins lCP4 or lCP27. Surprisingly, no increase in the trans-activation function of NF-kappa B, as assayed by transient expression of CAT, was detected following HSV infection. The significance of NF-kappa B nuclear translocation for virus replication was demonstrated by an 80-90% reduction in virus yield following infection of C33 cells expressing a constitutive repressor form of 1 kappa B alpha. Models that reconcile nuclear translocation of NF-kappa B with the inability to detect NF-kappa B-dependent gene expression are discussed.

Induction of interleukin-6 in human retinal epithelial cells by an attenuated Herpes simplex virus vector requires viral replication and NFκB activation

“…However, more detailed studies will be required to confirm this. Our findings are also consistent with several reports showing HSV induces a persistent activation of NF-κB in several cell types (Rong et al 1992;Patel et al 1998;Amici et al 2001;Taddeo et al 2003;Gregory et al 2004;Hargett et al 2006).…”

“…The activation of NF-κB at 3-4 h post-infection in ARPE-19 cells is similar to the timing of NF-κB activation in other cell types infected with HSV (Patel et al 1998;Amici et al 2001;Goodkin et al 2003;Taddeo et al 2003;Amici et al 2006). A transient activation of NF-κB that occurs immediately upon infection has also been reported to occur in a human keratinocyte cell line (HaCaT) (Amici et al 2006).…”

“…The IL-6 promoter contains binding sites for nuclear factor κB (NF-κB) and the requirement of NF-κB activation for IL-6 induction has been well documented (Rong et al 1992;Matsusaka et al 1993;Patel et al 1998;Amici et al 2001;Paludan 2001;Hargett et al 2006;Melchjorsen et al 2006). We therefore asked if NF-κB was activated in hrR3 infected ARPE-19 cells by measuring translocation of NF-κB from the cytoplasm to the nucleus.…”

“…The IL-6 promoter contains consensus binding sites for the NF-κB family of transcription factors and NF-κB is required for the induction of IL-6 as well as other genes in several cell types (www.nf-kb.org; (Rong et al 1992;Matsusaka et al 1993;Patel et al 1998;Amici et al 2001;Paludan 2001;Hargett et al 2006;Melchjorsen et al 2006). There are seven different NF-κB family proteins that dimerize to form 15 possible complexes: p105, p50, p100, p52, p65, c-rel, and RelB.…”

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

“…The limited effect of TSA was associated with NF-kB's activation by this HDACi. 18 With regard to HSV infections, NF-kB is activated early during an HSV-1 infection, translocates to the nucleus 24,25 and prevents virus-induced early apoptosis of infected cells to complete its replication cycle. [25][26][27] Whether an HDACi that activates NF-kB could affect the replication of oncolytic HSV-1 mutants has not been investigated.…”