HHV Infected Cell Polypeptide 0 (ICP0)

Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein produced by Herpes viruses during the earliest stage of infection, when the herpes virus has recently entered the host cell. This stage is known as the immediate-early or α ("alpha") phase of Herpes virus gene expression.^[1]

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History and background

ICP0 was identified as an immediate-early polypeptide product of HSV-1 infection in 1976.^[2] The gene from which ICP0 is produced is known as HSV-1 α0 ("alpha zero") and formerly as Immediate Early (IE) gene 1. However, the gene is also referred to as the HSV-1 ICP0 gene. The HSV-1 ICP0 gene was characterized and sequenced in 1986.^[3] This sequence predicted a 775 amino acid sequence with a molecular weight of 78457 Da.^[3][4]

Antisense interaction with latency-associated RNA transcript (LAT)

During latent infection a viral RNA transcript inhibits expression of the Herpes virus ICP0 gene via an antisense RNA mechanism.^[5] The RNA transcript accumulates in host cells during latent infection and is known as Latency Associated Transcript (LAT).^[5] Study of the HSV-1 genome has located a chromatin insulator region between LAT and ICP0 gene promoters which may allow for the independent regulation of their expression.^[6]

ICP0 and homologs interact with host cell SUMO-1 protein and disrupt PML Nuclear Bodies

SUMO-1 is a ubiquitin-related protein produced by human cells.^[7][8] A normal function of SUMO-1 appears to be modification of the human PML protein so that PML localizes in the nucleus where it becomes a part of the PML nuclear bodies (or ND10 structures).^[7]

HSV-1 ICP0 and several of its homologs have been found to bind to SUMO-1 in a manner similar to endogenous proteins.^[9] HSV-1 ICP0-family proteins have also been shown to disrupt the formation of nuclear bodies in a manner which depends on this activity of ICP0.^[10][11] ICP0 expression has been shown to result in the depletion of cellular SUMO-1 and the disruption of PML nuclear bodies,^[12] while ICP0-homologs in other Herpes viruses have also been shown to disrupt PML nuclear bodies.^{[13][14][15][10]}

Protein cofactor interaction with neuron-differentiating protein NRSF

ICP0 may regulate the expression of some human genes and Herpes virus genes in infected cells.^[16][17] ICP0 may interact with a human protein, Neuronal Restrictive Silencer Factor (NRSF)^[18], which normally functions to regulate DNA differences between cells.^[19] Expression of NRSF determines whether each human cell is a neuron or non-neuronal cell.^[20][21] The HSV-1 genome contains an NRSF-binding domain near the beginning of the ICP4 and ICP22 immediate-early genes, which regulates their expression.^[17]

ICP0 is partially similar to the human protein CoREST^[16], and CoREST normally combines with Neuronal Restrictive Silencer Factor (NRSF, formerly REST^[22]) to repress expression of neuronal genes in nonneuronal cells.^[19][21] In non-neuronal cells, ICP0 may prevent the silencing of the HSV genome.^[18]

In neurons, truncated forms of NRSF may be produced in order to selectively express certain neurotransmitter channels in specialized neurons.^[20] In neurons, ICP0 may combine with NRSF-like neuronal factors to silence immediate-early genes, possibly blocking the production of ICP4 and possibly reducing production of ICP22.^[17] The repressed production of these immediate-early HSV genes may contribute to the establishment of latent HSV infection.^[17]

CoREST and NRSF normally combine with another cellular protein, histone deacetylase-1 (HDAC). A study confirms that this complex silences production of HSV-1 protein ICP4 via deacetylation of the histones around which viral DNA chromatin is packed.^[17] ICP0 interferes with the HDAC/CoREST/NRSF complex by dissociating HDAC1 from CoREST/NRSF. ^[16][18] An NRSF-binding DNA has been found between the viral genes expressing proteins ICP4 and ICP22.^[17]

Homologs across Herpes virus species

The HSV-1 ICP0 gene and protein have corresponding homologs in related viruses from the Herpes virus family. The reported sequence for HSV-2 ICP0 is predicted to produce a polypeptide comprised of 825 amino acids with a predicted molecular weight of 81986 Da, and 61.5% amino acid sequence similarity to HSV-1 ICP0.^[23][24] Simian Varicella Virus (SVV) is a Varicellovirus (a Genus of Subfamily Alphaherpesvirinae) which expresses an HHV LAT homolog known as SVV LAT, and an HHV ICP0 analog known as SVV ORF-61 (Open Reading Frame 61).^[25] 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^[26][27] for HSV-1 ICP0 gene.

Notes

• ICP0 blocks the Interferon pathway of cellular host antiviral response which otherwise would lead to production of RNase L and lead to host cell apoptosis. ^[29]