Background
The Herpesviridae family includes the neurotropic α-herpesvirus known as varicella-zoster virus (VZV), which is widely detected in people. In addition to producing shingles and varicella (chickenpox), VZV can lie dormant in the nerve ganglia of the human body and reawaken when the immune system is compromised. Primary VZV infection usually causes chickenpox, a highly contagious disease that mostly affects children. Varicella-zoster virus (VZV) can become dormant in the nervous system and reactivate when the immune system is weakened, resulting in shingles. This virus can multiply and propagate within the ganglia, resulting in an enhanced inflammatory response and neuronal death. Severe neuralgia is common, with the elderly suffering the most. Chickenpox is the primary infection caused by VZV, characterized by widespread rashes and fever. Due to its high contagion, chickenpox outbreaks often affect large numbers of unvaccinated children. While chickenpox is self-limiting in most cases, severe complications such as encephalitis and pneumonia can occur, especially in individuals with weakened immune systems, potentially leading to serious outcomes. On the other hand, shingles result from the reactivation of VZV within the nerve ganglia, usually presenting with unilateral painful rashes. The incidence and severity of shingles increase with age, with postherpetic neuralgia (PHN) being especially common. This neuralgia can persist for months or even years, severely affecting the patient's quality of life.
Vaccination is an essential preventive measure against VZV infection and the problems it can cause. The varicella vaccination has been widely used to lower the incidence of chickenpox drastically. The shingles vaccination has also demonstrated good preventive effects for shingles, especially in the older population. According to studies, shingles vaccination can lessen the risk of postherpetic neuralgia and cut the incidence of shingles in people over 50 by almost 50%. These vaccinations considerably lessen the burden on public health and safeguard individual health.
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Figure 1. Effective Composition of Adjuvanted Recombinant Herpes Zoster Vaccine (Source: Ishihara R, et al., 2024)
Among VZV's numerous membrane proteins, glycoprotein E (gE) is one of the most prominent and important. VZV's principal protective antigen is gE, which plays an important role in replication and dissemination. Because of its relevance, gE has become a key target in vaccine research. Recombinant subunit vaccines based on gE have already entered clinical trials, demonstrating considerable protective effects, particularly in the elderly population. Studies have shown that the gE subunit vaccination can greatly lower the incidence of shingles in people aged 50 and up, with an efficacy of up to 97.2% when compared to a placebo. Furthermore, gE has significant uses in the serological detection of VZV. Currently, gE-based detection methods, including Western blotting and immunofluorescence, are widely used for diagnosing VZV infection. However, quantitative detection methods targeting gE, such as enzyme-linked immunosorbent assay (ELISA), are still under development. Researchers have successfully developed a specific and sensitive sandwich ELISA detection method to quantitatively measure gE content in vaccines by purifying recombinant gE protein (rgE) expressed in insect cells. This technological breakthrough not only enhances the quality control capabilities of VZV vaccines but also provides powerful tools for further research on VZV and the development of related vaccines. Overall, VZV is not only the causative agent of chickenpox and shingles, but its associated gE protein also provides an important scientific basis for vaccine development and disease prevention. With ongoing vaccine research, we expect to see safer and more effective VZV vaccines in the future, further reducing the incidence of VZV-related diseases.
Alternative Names
Recombinant Varicella-Zoster Virus Glycoprotein E
VZV gE Recombinant Protein
References
- 1. Ishihara R, et al. Exploring the link between varicella-zoster virus, autoimmune diseases, and the role of recombinant zoster vaccine. Biomolecules. 2024;14(7):739.
References
Phosphorylation by the varicella-zoster virus ORF47 protein serine kinase determines whether endocytosed viral gE traffics to the trans-Golgi network or recycles to the cell membrane
JOURNAL OF VIROLOGY
Authors: Kenyon, TK; Cohen, JI; Grose, C
Abstract
Like all alphaherpesviruses, varicella-zoster virus (VZV) infection proceeds by both cell-cell spread and virion production. Virions are enveloped within vacuoles located near the trans-Golgi network (TGN), while in cell-cell spread, surface glycoproteins fuse cells into syncytia. In this report, we delineate a potential role for serine/threonine phosphorylation of the cytoplasmic tail of the predominant VZV glycoprotein, gE, in these processes. The fact that VZV gE (formerly called gpI) is phosphorylated has been documented (E. A. Montalvo and C. Grose, Proc. Nati. Acad. Sci. USA 83:8967-8971, 1986), although respective roles of viral and cellular protein kinases have never been delineated. VZV ORF47 is a viral serine protein kinase that recognized a consensus sequence similar to that of casein kinase II (CKII). During open reading frame 47 (ORF47)-specific in vitro kinase assays, ORF47 phosphorylated four residues in the cytoplasmic tail of VZV gE (S593, S595, T596, and T598), thus modifying the known phosphofurin acidic cluster sorting protein 1 domain. CKII phosphorylated gE predominantly on the two threonine residues. In wild-type-virus-infected cells, where ORF47-mediated phosphorylation predominated, gE endocytosed and relocalized to the TGN. In cells infected with a VZV ORF47-null mutant, internalized VZV gE recycled to the plasma membrane and did not localize to the TGN. The mutant virus also formed larger syncytia than the wild-type virus, linking CKII-mediated gE phosphorylation with increased cell-cell spread. Thus, ORF47 and CKII behaved as "team players" in the phosphorylation of VZV gE. Taken together, the results showed that phosphorylation of VZV gE by ORF47 or CKII determined whether VZV infection proceeded toward a pathway likely involved with either virion production or cell-cell spread.
Intracellular traffic of herpes simplex virus glycoprotein gE: Characterization of the sorting signals required for its trans-Golgi network localization
JOURNAL OF VIROLOGY
Authors: Alconada, A; Bauer, U; Sodeik, B; Hoflack, B
Abstract
Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are two pathogenic human alphaherpesviruses whose intracellular assembly is thought to follow different pathways. VZV presumably acquires its envelope in the trans-Golgi network (TGN), and it has recently been shown that its major envelope glycoprotein, VZV-gE, accumulates in this compartment when expressed alone. In contrast, the envelopment of HSV has been proposed to occur at the inner nuclear membrane, although to which compartment the gE homolog (HSV-gE) is transported is unknown. For this reason, we have studied the intracellular traffic of HSV-gE and have found that this glycoprotein accumulates at steady state in the TGN, both when expressed from cloned cDNA and in HSV-infected cells. In addition, HSV-gE cycles between the TGN and the cell surface and requires a conserved tyrosine-containing motif within its cytoplasmic tail for proper trafficking. These results show that VZV gE and HSV-gE have similar intracellular trafficking pathways, probably reflecting the presence of similar sorting signals in the cytoplasmic domains of both molecules, and suggest that the respective viruses, VZV and HSV, could use the same subcellular organelle, the TGN, for their envelopment.
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