Varicella Zoster Virus: gE, IE-62 and IE-63 essential for Infection
February 27, 2025
Dr. Lilian Schoefer
Research updates
Research updates
The Varicella Zoster Virus (VZV), also known as Human Herpesvirus 3 (HHV-3), is a member of the alphaherpesvirus subfamily within the Orthoherpesviridae. When it infects a person for the first time, it causes chickenpox. In contrast, reactivation of the virus results in shingles.
Taxonomy: Viruses > Duplodnaviria > Heunggongvirae > Peploviricota > Herviviricetes > Herpesvirales > Orthoherpesviridae > Alphaherpesvirinae > Varicellovirus > Varicellovirus humanalpha3 > Human herpesvirus 3 (HHV-3)
Envelope contains immunogenic glycoproteins
With its lipid bilayer envelope, the Varicella Zoster Virus (VZV) reaches a size of between 180 and 200 nm in diameter. Embedded within the lipid bilayer are glycoproteins, which enable the virion to attach to the host cell and fuse both membranes. The VZV genome contains eleven open reading frames encoding membrane-associated glycoproteins, with the most common ones being:
- Glycoprotein gE
- Glycoprotein gB
- Glycoprotein gH
Glycoprotein E (gE) is highly immunogenic and considered the primary target of varicella zoster-specific CD4+ T cell reactions. [1]Accordingly, it is a key component of the Shingrix vaccine. [2]
Glycoprotein gE as Peptide Pool
We provide glycoprotein gE as VZV gE peptide pool, which is a valuable tool for scientists. The peptide pool stimulates a strong, specific T cell response and is used to:
- develop vaccines against the varicella zoster virus
- elucidate the underlying pathomechanisms of varicella zoster-associated diseases
- investigate the impact of immunosuppressive therapeutics on immunity against varicella zoster.
In the lipid bilayer, the glycoproteins can form heterodimers: gE with gI and gH with gL, for example. In addition, the membrane of the varicella zoster virus contains the glycoproteins gC, gK, gN, gM, ORF39 and ORFS/L.
Viral proteins in the tegument
Between the lipid bilayer and the nucleocapsid of the varicella zoster virus there is a mixture of loosely associated viral proteins - the tegument. The immediate-early proteins IE62 and IE63 are located there. They are essential for the successful replication of the varicella zoster virus.
Immediate-early protein 62 (IE62): the viral transactivator
The VZV immediate early 62 protein (IE62) is the most important viral transactivator and therefore essential for viral growth. [3] IE62 comprises 1,310 amino acids and is also known as major viral transcription factor ICP4 homolog. This tegument protein is introduced into the nuclei of freshly infected cells, where it acts as a transcriptional transactivator: It initiates the replication of the varicella zoster virus by transactivating viral immediate early, early and late genes. To do this, IE62 interacts with components of the host cell's transcription apparatus and recruits them to viral promoters.
IE62 binds cellular transcription factors such as:
- upstream stimulatory factor (USF)
- TATA-binding protein (TBP)
- TFIIB
- Sp1
It also interacts with several viral proteins such as:
- ORF63 (IE63)
- ORF4 (IE4)
- ORF9
- ORF47.
IE62 negatively regulates its own transcription.
With our peptide IE62 593-601 (HLA-A*02:01) we offer an epitope of the Immediate Early 62 protein for immunological studies. IE62 593-601 has the amino acid sequence ALWALPHAA and a purity of 95% (HPLC-MS).
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Immediate Early 63-kDa protein (IE63): anti host, pro virus
The immediate early 63-kDa protein (IE63) is a phosphoprotein that is also known as transcriptional transactivator IE63 and transcriptional regulator ICP22 homolog. In the first stage of infection, IE63 is primarily expressed in the host cell's nucleus, where it interacts with transcription factors and RNA polymerases, including:
- GTF2E1
- GTF2H2
- POLR2A
These interactions enable IE63 to regulate the transcription of both cellular and viral mRNAs. As mentioned above, IE63 modulates the function of IE62 – the most important viral transactivator. By disorganizing specific promoters, IE63 also helps to suppress the host‘s innate immune response to the virus. Furthermore, IE63 can interact with host proteins, such as ASF1, altering their ability to bind histones. [4] During viral latency, IE63 is predominantly localized in the cytoplasm.
Our VZV (IE63) Peptide Pool covers the complete immediate early 63-kDa protein of the varicella-zoster virus (strain Oka vaccine). It contains 67 15-mers that overlap by 11 amino acids, allowing for optimal T cell assays in immunological investigations of the protein.
Not all tegument proteins characterized
There are other tegument proteins, but not all of them have been characterized yet. In addition to regulating gene expression and immune evasion in the host cell, their functions include:
- capsid transport during entry and egress
- targeting of the capsid to the nucleus
- cytoskeletal assembly
- viral assembly
Nucleocapsid in icosahedral form
The nucleocapsid of the varicella zoster virus consists of 162 capsomeres that form an icosahedron. It has a diameter of about 100 nm. The capsomeres are made up of four different proteins that are arranged in a specific pattern. The major capsid protein (MCP) can form hexamers or pentamers. The small capsid protein (SCP) is positioned on top of the major capsid protein hexamers. In between are heterotrimers made up of the proteins Tri1 and Tri2.
Double-stranded, circular DNA
The capsid contains a double-stranded, circular DNA (dsDNA) with a length of about 125 kb. It contains at least 70 open reading frames that encode viral proteins.[5]
The genome consists of two major coding regions: the unique long (UL) and the unique short (US) regions. Both are flanked by internal and terminal repeats. The open reading frames ORF63/70, ORF62/71 and ORF64/69 are located within the repeats and are therefore duplicated in the varicella zoster virus genome.
The duplicated ORFs 62 and 71 encode the immediate early 62 protein (IE62). Both open reading frames are located within the inverted repeats that delimit the US region of the VZV genome. ORF63 and ORF70 encode the immediate early 63-kDa protein (IE63).
Primary VZV infection causes chickenpox
A primary infection with the varicella-zoster virus leads to varicella or chickenpox, typically in childhood, through droplet transmission or direct contact. The virus replicates in the epithelial lining of the respiratory tract, followed by viremia. [6] This results in the development of the characteristic exanthema and enanthema. Notably, patients are already infectious a few days before the blisters appear.
As the blisters dry and crusts form, infection is significantly less likely. Pregnant women infected with the virus can transmit it to their unborn child. In immunosuppressed patients, complications such as necrotizing, ulcerating, hemorrhagic, and generalized forms of the disease may occur.
The varicella-zoster virus is highly contagious and remains latent in the body after the primary infection. In industrialized countries, approximately 90% of 15-year-olds carry the virus. However, the exact pathomechanism underlying latency in the dorsal root ganglia is not yet fully understood.
Reactivated VZV causes herpes zoster
When reactivated, the varicella zoster virus spreads neurotropically and epidermotropically on the skin's surface, resulting in the clinical manifestation of herpes zoster or shingles. This condition is often accompanied by severe acute pain.
The virus typically targets one or more dermatomes, which are areas of skin innervated by a single sensory nerve. The incidence of herpes zoster increases with age, but individuals of any age can be affected.
In approximately 80% of patients, prodromal symptoms occur before the onset of shingles. These prodromes manifest as pain in the corresponding dermatome, often accompanied by non-specific general symptoms. Following the prodromal stage, grouped vesicles develop on an erythematous base. These vesicles can occur in any dermatome, but are most commonly found in the thoracic or trigeminal region.
Involvement of several adjacent, overlapping dermatomes and symmetrical involvement of both body halves are rare. However, in immunosuppressed patients, necrotizing, multisegmental, or generalized courses of the disease can occur.
Involvement of Sensory Organs
Sensory organs can be involved in the trigeminal area, depending on the affected nerve branch. In case of herpes zoster ophthalmicus, this can lead to visual disturbances, paresis of the eye muscles and pain. If the eye is involved, conjunctivitis or keratitis are the most common. In cases where the V2 dermatome is affected, patients may experience:
- Headaches
- Earaches
- Failure of the facial nerve and vestibulocochlear nerve
Symptoms can include:
- Dizziness
- Hearing loss
- Weakness or paresis of the facial muscles (Ramsay Hunt syndrome)
While rare, manifestations of encephalitis or meningitis can occur.
Literature
- Leroux-Roels, Isabel et al. “A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein e subunit vaccine candidate in young and older adults.” The Journal of infectious diseases vol. 206,8 (2012): 1280-90. doi:10.1093/infdis/jis497
- https://www.ema.europa.eu/en/medicines/human/EPAR/shingrix
- Kim, Seong K et al. “Functional Characterization of the Serine-Rich Tract of Varicella-Zoster Virus IE62.” Journal of virology vol. 90,2 959-71. 4 Nov. 2015, doi:10.1128/JVI.02096-15
- https://www.uniprot.org/uniprotkb/Q77NN7/entry
- Baiker, Armin et al. “The immediate-early 63 protein of Varicella-Zoster virus: analysis of functional domains required for replication in vitro and for T-cell and skin tropism in the SCIDhu model in vivo.” Journal of virology vol. 78,3 (2004): 1181-94. doi:10.1128/jvi.78.3.1181-1194.2004
- Wilms, Larissa et al. “Infektionen mit Herpes-simplex- und Varizella-zoster-Virus.” Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG vol. 20,10 (2022): 1327-1353. doi:10.1111/ddg.14917_g
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