Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is aprotein, encoded by theDNA ofherpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the hostcell; this stage is known as theimmediate-early orα ("alpha") phase of viral gene expression.^[1] During these early stages of infection, ICP0 protein is synthesized and transported to thenucleus of the infected host cell. Here, ICP0 promotestranscription from viralgenes, disrupts structures in the nucleus known asnuclear dots or promyelocytic leukemia (PML) nuclear bodies,^[2] and alters the expression of host and viral genes in combination with aneuron specific protein.^[3][4] At later stages of cellular infection, ICP0 relocates to the cellcytoplasm to be incorporated into newvirion particles.^[5]

ICP0 was identified as an immediate-early polypeptide product ofHerpes simplex virus-1 (HSV-1) infection in 1976.^[6] Thegene, in HSV-1, from which ICP0 is produced is known asHSV-1 α0 ("alpha zero"),Immediate Early (IE) gene 1, or simply as theHSV-1 ICP0 gene. The HSV-1 ICP0 gene was characterized andsequenced in 1986.^[7] This sequence predicted a 775amino acid sequence with a molecular weight of 78.5KDa.^[7][8] At the time of gene isolation, ICP0 was known as IE110 asgel electrophoresis experiments performed prior to obtaining the gene sequence indicated the ICP0 protein weighed 110 kDa. Post-translational modifications, such asphosphorylation orsumoylation, were presumed to account for the actual protein size appearing 30 kDa larger than that of the predicted amino acid sequence.

ICP0 co-localizes with α-tubulin, and dismantles host cell microtubule networks once it translocates to the cytoplasm.^[9]

In HSV-1 infected cells, ICP0 activates the transcription of many viral and cellular genes. It acts synergistically with HSV-1 immediate early (IE) protein,ICP4, and is essential for the reactivation of latent herpes virus and viral replication.^[10]

ICP0 is responsible for overcoming a variety of cellular antiviral responses. After translocating to the nucleus early in infection, ICP0 promotes the degradation of many cellular antiviral genes, including those for nuclear body-associated proteins promyelocytic leukemia protein (PML) and Sp100, causing disruption of PML nuclear bodies and reduced cellular antiviral capacity.^[11][12] ICP0 also inhibits the activity of IFN regulatory factors (IRF3) andIRF7, which are keytranscription factors that induce production of antiviralcytokines calledinterferons.^[13]Barriers to viral replication induced by interferons can also be overcome by the action of ICP0.^[14] This function of ICP0 also prevents the production ofRNase L, an enzyme that degrades single-stranded viral and cellular RNAs and induces host cellapoptosis in virus infected cells.^[15]

Small ubiquitin-related modifier 1 (SUMO-1) is a protein produced by human cells that is involved in the modification of many proteins, including human PML protein.^[16][17][18]HSV-1 ICP0 and several of its homologs in other herpes viruses bind to SUMO-1 in a manner similar toendogenous proteins,^[19] causing depletion of SUMO-1, and disruption of nuclear bodies.^{[2][20][21][22][23][24]}

ICP0 interacts with a human protein, known as Neuronal Restrictive Silencer Factor (NRSF) orRE1-silencing transcription factor (REST)^[25][26] that regulates differences in gene expression between cells ofneuronal or non-neuronal origin; NRSF is found in non-neuronal cells but not in fullydifferentiated neurons.^[27] This interaction is attributed to the partial similarity of ICP0 to the human protein CoREST, also called REST corepressor 1 (RCOR1),^[3] which combines with NRSF to repress expression of neuronal genes in non-neuronal cells.^[27][28]

Although the full NRSF protein is not typically found in neurons, truncated forms of NRSF are produced that selectively control the expression of certainneurotransmitter channels in specialized neurons.^[29] Combination of ICP0 with these NRSF-like neuronal factors may silence herpes genes in neurons, blocking the production of other immediate-early genes such asICP4 and reducing production ofICP22.^[4] The repressed production of immediate-early HSV genes may contribute to the establishment oflatency during infection with herpes viruses.^[4]

CoREST and NRSF combine with another cellular protein,histone deacetylase-1 (HDAC) to form a HDAC/CoREST/NRSF complex. This complex silences production of the HSV-1 protein ICP4 by interfering withchromatin remodeling of the viral DNA that is necessary to allow viral genetranscription; itdeacetylateshistones associated with viral DNA in viralchromatin.^[4] Furthermore, an NRSF-binding region is located between the viral genes expressing proteins ICP4 and ICP22.^[4] ICP0 interacts with coREST, dissociating HDAC1 from CoREST/NRSF in the HDAC/CoREST/NRSF complex and preventing the silencing of the HSV genome in non-neuronal cells.^[3][25]

During latent infection a viralRNA transcript inhibits expression of the herpes virus ICP0 gene via anantisense RNA mechanism.^[30] The RNA transcript is produced by the virus and accumulates in host cells during latent infection; it is known asLatency Associated Transcript (LAT).^[30] Achromatin insulator region betweenpromoters of the LAT and ICP0 genes of the HSV-1 genome may allow for the independent regulation of their expression.^[31]

Although it is tempting to hypothesize that LAT is the repressor of the ICP0 gene, evidence supporting this hypothesis is lacking. Recent data suggest that ICP4 strongly suppresses the ICP0 gene, and ICP0 antagonizes ICP4.^[32] The balance between ICP0 and ICP4 dictates whether the ICP0 gene can be efficiently transcribed.^[32]

The ICP0 gene and protein from HSV-1 haveorthologs in related viruses from the herpes virus family. HSV-2 ICP0 is predicted to produce a polypeptide of 825 amino acids with a predicted molecular weight of 81986 Da, and 61.5% amino acid sequence similarity to HSV-1 ICP0.^[33][34]Simian varicella virus (SVV) is avaricellovirus that, like HSV-1 and HSV-2, belongs to thealphaherpesvirinae subfamily of herpes viruses. SVV expresses an HSV-1 LAT ortholog known as SVV LAT, and an HSV-1 ICP0 ortholog known as SVV ORF-61 (Open Reading Frame 61).^[35]Varicella Zoster Virus (VZV) is another varicellovirus in which a homolog of HSV-1 ICP0 gene has been identified; VSV ORF-61 is a partial homolog and a functional replacement for HSV-1 ICP0 gene.^[36][37]

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