Herpes Simplex Virus Disrupts NF-κB Regulation by Blocking Its Recruitment on the IκBα Promoter and Directing the Factor on Viral Genes

Abstract

Herpes simplex viruses (HSVs) are able to hijack the host-cell IκB kinase (IKK)/NF-κB pathway, which regulates critical cell functions from apoptosis to inflammatory responses; however, the molecular mechanisms involved and the outcome of the signaling dysregulation on the host-virus interaction are mostly unknown. Here we show that in human keratinocytes HSV-1 attains a sophisticated control of the IKK/NF-κB pathway, inducing two distinct temporally controlled waves of IKK activity and disrupting the NF-κB autoregulatory mechanism. Using chromatin immunoprecipitation we demonstrate that dysregulation of the NF-κB-response is mediated by a virus-induced block of NF-κB recruitment to the promoter of the IκBα gene, encoding the main NF-κB-inhibitor. We also show that HSV-1 redirects NF-κB recruitment to the promoter of ICP0, an immediate-early viral gene with a key role in promoting virus replication. The results reveal a new level of control of cellular functions by invading viruses and suggest that persistent NF-κB activation in HSV-1-infected cells, rather than being a host response to the virus, may play a positive role in promoting efficient viral replication. Herpes simplex viruses (HSVs) are able to hijack the host-cell IκB kinase (IKK)/NF-κB pathway, which regulates critical cell functions from apoptosis to inflammatory responses; however, the molecular mechanisms involved and the outcome of the signaling dysregulation on the host-virus interaction are mostly unknown. Here we show that in human keratinocytes HSV-1 attains a sophisticated control of the IKK/NF-κB pathway, inducing two distinct temporally controlled waves of IKK activity and disrupting the NF-κB autoregulatory mechanism. Using chromatin immunoprecipitation we demonstrate that dysregulation of the NF-κB-response is mediated by a virus-induced block of NF-κB recruitment to the promoter of the IκBα gene, encoding the main NF-κB-inhibitor. We also show that HSV-1 redirects NF-κB recruitment to the promoter of ICP0, an immediate-early viral gene with a key role in promoting virus replication. The results reveal a new level of control of cellular functions by invading viruses and suggest that persistent NF-κB activation in HSV-1-infected cells, rather than being a host response to the virus, may play a positive role in promoting efficient viral replication. Herpes simplex virus type 1 (HSV-1) 4The abbreviations used are: HSV-1, herpes simplex virus type 1; ChIP, chromatin immunoprecipitation; CPE50%, 50% cytopathic effect; ICP0, infected cell protein 0; IκBα, κB inhibitory protein α; IKK, IκB kinase; NF-κB, nuclear factor-κB; PGA1, prostaglandin A1; p.i., post infection; IE, immediate-early gene; DE, delayed-early gene; L, late gene; EMSA, electrophoretic mobility shift assay.4The abbreviations used are: HSV-1, herpes simplex virus type 1; ChIP, chromatin immunoprecipitation; CPE50%, 50% cytopathic effect; ICP0, infected cell protein 0; IκBα, κB inhibitory protein α; IKK, IκB kinase; NF-κB, nuclear factor-κB; PGA1, prostaglandin A1; p.i., post infection; IE, immediate-early gene; DE, delayed-early gene; L, late gene; EMSA, electrophoretic mobility shift assay. represents a prototype for understanding the fundamental replication mechanisms of herpesviruses, a large family of medically important double-stranded DNA viruses. As other members of the family, HSV-1 can establish productive and latent infections (1Roizman B. Knipe D.M. Knipe B.N. Howley P.M. Fields Virology. 4th. 2. Lippincott Williams & Wilkins, Philadelphia, PA2001: 2399-2459Google Scholar). During productive infection HSV-1 efficiently redirects the host transcriptional machinery to express its own genes in a tightly regulated temporal cascade, consisting of the sequential expression of three gene classes: the immediate-early (IE), delayed-early (DE) and late (L) genes. The five IE genes are expressed shortly after entry into the host cell, and the resulting IE proteins (infected cell proteins ICP-0, -4, -22, -27, and -47) are essential for the subsequent temporally controlled expression of DE genes, the majority of which encode proteins involved in viral DNA replication, as well as of later L genes, which encode predominantly structural proteins. In particular, the multifunctional phosphoprotein ICP0 acts as a strong activator of all classes of HSV-1 genes, as well as of other eukaryotic genes (1Roizman B. Knipe D.M. Knipe B.N. Howley P.M. Fields Virology. 4th. 2. Lippincott Williams & Wilkins, Philadelphia, PA2001: 2399-2459Google Scholar). The molecular mechanism responsible for ICP0 transactivating activity is not yet understood. No specific DNA-binding sequence for ICP0 could be identified, and the transactivating activity seems to be dependent on one or more of the different functions of the ICP0 protein (2Everett R.D. BioEssays. 2000; 22: 761-770Crossref PubMed Scopus (254) Google Scholar). The facts that ICP0-negative mutants grow poorly in most tissue systems and are reactivation-impaired indicate that adequate ICP0 activity confers a growth advantage and is essential to promote initiation of the lytic-phase transcriptional events (1Roizman B. Knipe D.M. Knipe B.N. Howley P.M. Fields Virology. 4th. 2. Lippincott Williams & Wilkins, Philadelphia, PA2001: 2399-2459Google Scholar). Several distinct cis-acting elements are important for ICP0 expression during productive infection (3Davido D.J. Leib D.A. J. Gen. Virol. 1998; 79: 2093-2098Crossref PubMed Scopus (19) Google Scholar). In addition to the transactivating activity of the virion VP16 protein-induced complex, ICP0 expression can be modulated by a variety of host-transactivating factors, including the nuclear factor-κB(NF-κB). NF-κB is a collective term referring to a class of dimeric transcription factors consisting of homo- and heterodimers of five structurally related Rel/NF-κB proteins (4Santoro M.G. Rossi A. Amici C. EMBO J. 2003; 22: 2552-2560Crossref PubMed Scopus (314) Google Scholar). In most cells NF-κB exists as an inactive cytoplasmic complex, whose predominant form is a heterodimer composed of p50 and p65/RelA subunits, bound to inhibitory proteins of the IκB family, including IκBα, IκBβ, and IκBϵ (5Ghosh S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4597) Google Scholar). IκB proteins consist of an N-terminal regulatory domain followed by a series of ankyrin repeats important in the binding to the NF-κB heterodimer. The interaction with IκB masks the nuclear localization sequence in the NF-κB complex, sequestering the factor in the cytoplasmic compartment. Different stimuli for NF-κB activation initiate different signal transduction pathways most of which converge on the IκB kinase (IKK) signalosome that plays a major role in NF-κB activation (6Karin M. Ben-Neriah Y. Annu. Rev. Immunol. 2000; 18: 621-663Crossref PubMed Scopus (4073) Google Scholar). IKK is a multisubunit complex, containing two catalytic subunits (IKK-α and IKK-β), which are able to form homo- or heterodimers, and the IKK-γ or NEMO regulatory subunit, which is not a kinase per se, but acts as a docking protein for IKK kinases or other signaling proteins (7Israel A. Trends Cell Biol. 2000; 10: 129-133Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar). Following stimulation, the NF-κB/IκB complex is activated via the phosphorylation of the inhibitory protein. In the case of IκBα, IKK-mediated phosphorylation occurs at serine residues 32 and 36 in the N-terminal portion of the molecule (6Karin M. Ben-Neriah Y. Annu. Rev. Immunol. 2000; 18: 621-663Crossref PubMed Scopus (4073) Google Scholar). Phosphorylation targets IκBα for ubiquitination by the β-TrCP (transducin repeat-containing protein)-containing SCF (Skp1-Cul1-F-box-protein) ubiquitin ligase complex at lysines 21 and 22, which leads to degradation of the inhibitory subunit by the 26 S proteasome, allowing the release of NF-κB. Following the degradation of the inhibitory protein and exposure of the nuclear localization sequence motif, freed NF-κB dimers translocate to the nucleus and bind to DNA consensus sequences (κB elements), activating the transcription of several target genes, including the NF-κB-inhibitory protein IκBα, which provides a negative feedback mechanism to limit NF-κB activity (8Karin M. Cao Y. Greten F.R. Li Z. Cancer. 2002; 2: 301-310PubMed Google Scholar). IκBα displays nucleocytoplasmic shuttling properties and, after NF-κB-dependent resynthesis, it enters the nucleus and promotes NF-κB removal from DNA, restoring the inducible pool of the transcription factor into the cytoplasm (9Ghosh S. Karin M. Cell. 2002; 109: 81-96Abstract Full Text Full Text PDF PubMed Scopus (3286) Google Scholar). NF-κB was found to be activated early during HSV-1 infection (10Patel A. Hanson J. McLean T.I. Olgiate J. Hilton M. Miller W.E. Bachenheimer S.L. Virology. 1998; 247: 212-222Crossref PubMed Scopus (143) Google Scholar, 11Amici C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google and was to be involved in of several host genes B. A. B. S. A. 2002; PubMed Scopus Google as well as in promoting the of the virus replication C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, Bachenheimer S.L. J. Virol. PubMed Scopus Google Scholar). the mechanisms NF-κB activity in the nucleus of HSV-1-infected cells not In the we show in its target cell, the human HSV-1 infection two temporally controlled waves of IKK activity with distinct the we demonstrate that the virus NF-κB to the ICP0 ICP0 gene We also demonstrate during the of IKK the virus the NF-κB autoregulatory by with the recruitment of the factor to the IκBα The results new on viruses sophisticated control mechanisms to the cellular signaling machinery to own Cell and keratinocytes at in a in essential with and to the cell infected for 1 at with HSV-1 at a of infection of by or by cytopathic 50% on cell C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). HSV-1 virus was by exposure to on for exposure HSV-1 by as by assay. was after the and in the for the of the was for expressed as the and of and of a Cell with of the ICP0 promoter from to from the of was into the cells, which the HSV-1 in chromatin the promoter was with and by for of cells for after HSV-1 the of the used in the the to sequence of the was by the viral HSV-1 DNA and The was into the and the was by DNA cell after in a A. G. Y. Karin M. Santoro M.G. 2000; PubMed Scopus Google with κB DNA A. G. Santoro M.G. S. A. PubMed Scopus Google followed by of DNA-binding activity by as A. G. Santoro M.G. S. A. PubMed Scopus Google Scholar). by of was by with specific for of complex was by with the of and with in the of of at for IKK activity was as C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). of protein from cell by to and with or followed by with or C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). by for protein and transcription in as C. Santoro M.G. S. A. PubMed Scopus Google Scholar). was with containing for HSV-1 ICP0 human IκBα or gene, as a Following by and the was by of protein cells with cells, and in L containing the of by and for C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). cells by to the to a of cells with containing 1 and cells in and and for at at removal of in and chromatin was by removal of nuclear by at for at with and for of 50% protein was at and with protein or as control for three with and with 1 with containing by at DNA was with and with of as was at for at for and at for specific for the human IκBα promoter and for the ICP0 viral promoter and for the viral promoter and the form of the ICP0 promoter from the viral promoter in the we the but different the ICP0 gene for the viral form and the for the HSV-1 a of NF-κB in herpes simplex viruses the IKK/NF-κB in human cell infected with HSV-1 for at the virus was and cells at in essential with cells In a cell to or HSV-1, to virus replication was for NF-κB after the and at different post infection cell and for IKK activity by kinase IκBα degradation by and NF-κB activation by In human HSV-1 infection was found to IKK in a During virus a of IKK activity was IKK activation at was and of virus replication, it also after exposure of cells to of IKK was followed by IκBα degradation and of NF-κB DNA-binding which for As NF-κB on IκBα resynthesis, restoring the pool of the inhibitory protein and, activating the NF-κB autoregulatory signal later p.i., HSV-1 infection a of IKK activity from the early of at for several of IKK activity was dependent on virus replication, virus to it on The of IKK activity also to IκBα and it and persistent NF-κB activation and however, IκBα was to that HSV-1 could with the NF-κB autoregulatory at of In the of the inhibitory NF-κB in the activated DNA-binding for at in HSV-1-infected keratinocytes of IKK and NF-κB activity by HSV-1 in cells to HSV-1 for 1 at and at different p.i., cell from or cells for NF-κB activation by and for IKK activity and by kinase and of from are of IKK and NF-κB activity by and expressed as of control of NF-κB to the IκBα during HSV-1 the of IκBα the of IKK activity was the of a of cell protein after viral cells infected with HSV-1, and, at different cellular and viral protein was by and after In cell by for NF-κB activity and by for of As two of NF-κB activity after the and at p.i., As by into HSV-1 was found not to protein in the host cell to after infection In of after of proteins not reveal major in cellular protein in infected cells to not the that the of IκBα could be the of a protein at The of the IκBα gene transcription was by in on from As in IκBα transcription was virus The transcription a at the of the virus to IκBα at and to at IκBα gene transcription was not at later p.i., NF-κB DNA-binding activity and that NF-κB are to cellular target gene at of members of the Rel/NF-κB family as a of the DNA-binding complex not the that the in IκBα gene could be to the of inactive NF-κB the other control gene transcription not by the virus to NF-κB recruitment to the IκBα promoter was in by in HSV-1-infected and infected keratinocytes at different chromatin from cells with an DNA from was by to an of the IκBα promoter in the The of was at all not chromatin The of chromatin immunoprecipitation was by a control The virus entry was found to a recruitment of to the IκBα gene promoter gene to of IκBα by 1 p.i., as in IκBα is to the removal of from its promoter gene As recruitment of to the IκBα promoter IκBα to 1 and and recruitment could not be on at later p.i., that the in IκBα gene transcription is to an of NF-κB recruitment to the promoter of target NF-κB to the ICP0 during HSV-1 NF-κB binding elements in the promoter as well as in the of the HSV-1 ICP0 gene M. A. Immunol. 2002; PubMed Scopus Google Scholar). is the of NF-κB for of ICP0 gene We NF-κB is to the viral ICP0 gene cells infected with HSV-1 and by DNA was by with the ICP0 viral promoter was used as The viral promoter was also with specific in the In a viral ICP0 and cellular IκBα transcription by in on to the IκBα gene, was found to be to the ICP0 promoter after virus entry into the host cell ICP0, p65/RelA recruitment to the ICP0 promoter with a in ICP0 transcription that NF-κB bound to the viral may to ICP0 transcriptional recruitment to the ICP0 promoter was also at p.i., IκBα and NF-κB DNA-binding activity p65/RelA recruitment to the viral promoter for several by a in ICP0 gene which at No of chromatin with the was to the which NF-κB consensus the of on the ICP0 promoter ICP0 for the in NF-κB recruitment could be a of the different of viral and cellular DNA we cells in which the ICP0 promoter the expression of the gene is into the chromatin cells infected with HSV-1, and, at different for or As in HSV-1 infection activity in cells, that the promoter is activated by the In the NF-κB recruitment to the and to the viral ICP0 was at the of the virus and at which to the and waves of NF-κB the form of the ICP0 promoter from the viral promoter in the we the but different As in at the of the NF-κB is to the IκBα promoter and to and of the ICP0 that during the of NF-κB activation all the in to NF-κB As at NF-κB was not to the IκBα at NF-κB was to the viral form of the ICP0 into the host chromatin the ICP0 promoter its to the nuclear IκBα results suggest that the in NF-κB recruitment ICP0 and IκBα could be to in the of DNA to chromatin by HSV-1 during The IKK to the ICP0 and that are of NF-κB activation by and of the IKK A. G. Y. Karin M. Santoro M.G. 2000; PubMed Scopus Google Scholar). We the of the on NF-κB activation and recruitment to the ICP0 promoter in human cells infected with HSV-1 and with or control after the infected cells p.i., cell for NF-κB activity by and IκBα degradation by As in with IκBα degradation and NF-κB activation by HSV-1 in cell of NF-κB activity in the block of recruitment to the ICP0 promoter as by in infected cells the of on ICP0 cells with the cells infected or infected with HSV-1 and with after the As in in of viral as by As in other of cells, was in virus in HSV-1-infected as by at are also to with the activity of the transcription factor 1 A. G. Santoro M.G. S. A. PubMed Scopus Google Scholar, C. Santoro M.G. S. A. PubMed Scopus Google it be that different mechanisms could to the activity of in The nuclear factor NF-κB is a key of cellular in in the promoter of more than cellular genes whose expression is dependent on a sophisticated control of the factor by NF-κB target genes the NF-κB-inhibitory proteins and IκBα, which a negative feedback mechanism to limit NF-κB and several proteins that in the control of cell and as well as in the activation of the host and inflammatory (8Karin M. Cao Y. Greten F.R. Li Z. Cancer. 2002; 2: 301-310PubMed Google Scholar, M. A. Immunol. 2002; PubMed Scopus Google Scholar). important also in the of several including different members of the family S. Cao Virology. PubMed Scopus Google Scholar, J. Virol. PubMed Google Scholar). In of the role of NF-κB in cellular events and of the that activation of the NF-κB not protein NF-κB is an for the invading virus to control cellular human viral different to the NF-κB (4Santoro M.G. Rossi A. Amici C. EMBO J. 2003; 22: 2552-2560Crossref PubMed Scopus (314) Google Scholar). herpesviruses, it that the and the virus are of NF-κB activation an of of NF-κB M. A. A. J. J. Biol. 2000; PubMed Scopus Google Scholar, J. Virol. 2001; PubMed Scopus Google Scholar, EMBO J. PubMed Scopus Google Scholar, J. Scopus Google Scholar). we show that also are able to NF-κB in a In human keratinocytes HSV-1 a of NF-κB activation dependent on a and of IKK which a the control level at the of the virus IKK activity at is of virus replication, it occurs also after exposure of cells to that activation could be by the binding of the to cellular as the entry a of the M. M. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of IKK at is and is followed by IκBα degradation and of NF-κB DNA-binding NF-κB on IκBα resynthesis, restoring the pool of the inhibitory protein and activating the autoregulatory later after a of IKK activity is by HSV-1, which virus replication and viral protein C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). of IKK activity also IκBα inducing NF-κB IκBα occurs at of and, in the of the inhibitory NF-κB in the activated DNA-binding for at in HSV-1-infected persistent activation of NF-κB in different of and cells, to be a response of human cells to HSV-1 and to play an important role in viral (4Santoro M.G. Rossi A. Amici C. EMBO J. 2003; 22: 2552-2560Crossref PubMed Scopus (314) Google Scholar, 11Amici C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, C. Belardo G. Santoro M.G. 18: PubMed Scopus Google Scholar). the mechanism of NF-κB was not We that the of IκBα the of IKK activity is not the of a of cell protein after viral infection and be to degradation of IκBα as in cells infected with HSV-1 B. B. S. A. 2003; PubMed Scopus Google but is to a block of IκBα gene as by in assay. we demonstrate that the in IκBα gene transcription after the of NF-κB activation is to an of NF-κB recruitment to the promoter of target of HSV-1-infected keratinocytes show NF-κB activated during the is to the IκBα gene promoter gene and to of IκBα at 1 p.i., the factor could not be on at later we could not recruitment of NF-κB also on of other cellular target genes, as and not we show for the that NF-κB is to the viral ICP0 from the IκBα binding was on ICP0 waves of virus-induced NF-κB to ICP0 transcription at of The from the results that NF-κB activated at in human keratinocytes during HSV-1 infection is to viral gene it to to the promoter of its own IκBα after The mechanism responsible for the recruitment of the nuclear factor is at the The of NF-κB recruitment to the IκBα promoter could be to the sequestering of the factor by the of viral DNA in infected the that is not to the IκBα promoter at early of infection that for κB binding could be to Different could be In transcriptional gene factors as DNA or of During latent infection the HSV-1 is predominantly as and may play a regulatory role during HSV-1 J. Virol. PubMed Scopus Google Scholar, J. Virol. PubMed Scopus Google Scholar). the it is and at which HSV-1 DNA is bound to during In to of HSV-1 DNA J. Virol. PubMed Google Scholar, J. Gen. Virol. PubMed Scopus Google viral DNA found to with also during infection J. S.L. J. Virol. PubMed Scopus Google Scholar). its on IE gene and DE and L viral gene was not on IE which in as DNA in early of infection J. Virol. PubMed Scopus Google Scholar). In it that the in NF-κB recruitment to the ICP0 and IκBα during the of NF-κB activation could in the of viral and cellular DNA and it could be that chromatin by HSV-1 infection could the recruitment of NF-κB to its consensus sequences on the of cellular genes. the it could be into the chromatin the ICP0 promoter a cellular promoter in to NF-κB we cells in which the ICP0 promoter the expression of the gene is into the cellular chromatin The results indicate during the of NF-κB is not to the ICP0 promoter into the host the that major in chromatin and are involved in the of the factor on the viral for the recruitment of NF-κB to the viral promoter could be the of the virus to with the phosphorylation or of the factor in that NF-κB binding to DNA is controlled by phosphorylation of the p65/RelA subunit by different stimuli Rev. Cell Biol. PubMed Scopus Google Scholar). In of the of HSV-1 to the of several cellular kinases (1Roizman B. Knipe D.M. Knipe B.N. Howley P.M. Fields Virology. 4th. 2. Lippincott Williams & Wilkins, Philadelphia, PA2001: 2399-2459Google the of virus-induced of the transcription factor represents an important to be is the of the activated NF-κB in HSV-1-infected two to NF-κB activation during HSV-1 to viral replication and to block NF-κB activation seems to be to block apoptosis by or virus replication J. Virol. 2003; PubMed Scopus Google Scholar). virus mutants to NF-κB activation found to cells more to apoptosis J. Virol. 2003; PubMed Scopus Google Scholar). HSV-1 not apoptosis in cells in which NF-κB was not activated or and apoptosis is not in cells infected with the B. B. S. A. 2003; PubMed Scopus Google Scholar, B. B. J. Virol. PubMed Scopus Google Scholar). Several of show that NF-κB is by HSV-1 to its replication by the of NF-κB-dependent cellular proteins B. A. B. S. A. 2002; PubMed Scopus Google or by of viral C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, Bachenheimer S.L. J. Virol. PubMed Scopus Google Scholar). of NF-κB in the of the virus replication was by the that of NF-κB activity by the form of IκB in which residues critical for phosphorylation by IKK are by transcription of viral genes and virus in human cells (10Patel A. Hanson J. McLean T.I. Olgiate J. Hilton M. Miller W.E. Bachenheimer S.L. Virology. 1998; 247: 212-222Crossref PubMed Scopus (143) Google Scholar, 11Amici C. Belardo G. Rossi A. Santoro M.G. J. Biol. Chem. 2001; 276: 28759-28766Abstract Full Text Full Text PDF PubMed Scopus Google Scholar). In of or to in of viral in HSV-1-infected Bachenheimer S.L. J. Virol. PubMed Scopus Google Scholar). We demonstrate that NF-κB is in for several to the viral ICP0 to ICP0 virus-induced NF-κB activation by the IKK a block in viral resulting in of HSV-1 replication and in a in viral by infected results suggest that persistent NF-κB activation in HSV-1-infected cells, rather than being a host response to the virus, may play a positive role in promoting efficient viral replication. In the results reveal a new sophisticated level of control of cellular functions by invading viruses. We that HSV-1 not the cellular transcription factor it for its replication but is also able to the autoregulatory mechanism of NF-κB, it in a the of events involved in the of NF-κB and chromatin for recruitment of the factor is from being the understanding of human HSV-1 may with cellular is a the results indicate that in may to the of for We for the of the