Background
Varicella-zoster virus, also known as human herpesvirus type 3 (HHV-3), belongs to the family Herpesviridae and subfamily Alphaherpesvirinae. It has humans as its only natural host and has only one serotype. Virus particles have a diameter of 180~200nm, are round or polygonal, and have a DNA core in the center. The nucleocapsid is about 100nm in diameter and consists of 162 hexagonal shell particles arranged in an icosahedron with a central hollow axis and 5:3:2 axial symmetry; the nucleocapsid is surrounded by an inner membrane and an envelope partially derived from the cell membrane. The VZV genome is a double-stranded linear DNA about 125,000 bp in length, with a relative molecular mass of (80±3)×106, and 74 open reading frames (ORFs) encoding at least 71 viral gene products. DNA consists of two unique segments, UL (Uniquelongregion) and US (Uniqueshortregion), which are flanked by inverted repeats. UL is about 105kbp long, US is about 5232bp long. The two ends of the UL region are inverted repeat sequences TRL (Terminallongrepeats) and IRL (Internallongrepeats) about 88bp long, while the two ends of the US region are inverted repeat sequence IRS about 7319bp long. (Internalshortrepeats) and TRS (Terminalshortrepeats). In addition to the TRLUL-IRL-IRS-US-TRS genome structure, the genome also contains 6 tandem repeat sequence regions rich in guanine (G) and cytosine (C), namely R1, R2, R3, R4a, R5, and R4b, in which mutations often occur in the R3 region. Since the lipid envelope of the VZV virus is easily degraded by organic solvents, detergents, proteases, etc., causing the virus to lose its infectivity, VZV has weak resistance in vitro and is not resistant to acids and alkali. It cannot survive in scabs, but the blister fluid the virus can survive for a long time at -65°C. The virus can be inactivated in ether and room temperature for 1 hour. After initial infection with VZV, the virus infects T cells in the upper respiratory tract, epithelial cells, and tonsils, resulting in transient local replication. Under the action of non-specific immunity, interferon (IFN) begins to be produced in the blood; later, as the phosphorylation of STAT-1 molecules is blocked, IFN-α expression is restricted, and the first viremia occurs 4 to 6 days after infection. At the same time, the virus further multiplied in the liver and spleen of the reticuloendothelial tissue. About 14 days after infection, a second viremia occurred, and cell damage and inflammatory reactions were shown in the skin and mucous membranes. After passing through the rash and papule stages, it develops into blisters filled with clear fluid (containing virus particles) located in the superficial dermis layer of the skin.
Figure 1. VZV life cycle and replication.( Source: Zerboni L, et al., 2014)
After initial infection, VZV virus remains latent in dorsal horn neurons of the spinal cord and is periodically reactivated with subclinical reactivation of endogenous infection and occasional external contact with VZV virus to maintain immunity. As age increases or the body's immunity temporarily declines, cell-mediated immune function weakens below the critical threshold level of anti-VZV immunity, resulting in the occurrence of a unilateral vesicular rash accompanied by radicular pain, that is, herpes zoster.
VZV is a double-stranded DNA virus with a full length of about 125,000 bp and encodes 71 ORFs. The virus surface contains a variety of glycoproteins, among which glycoprotein E (gE) is the main surface structural protein of VZV and an important neutralizing protein. Antigens are highly conserved. Glycoprotein gE is a type I transmembrane protein with a total size of 623 amino acids. It is mainly divided into several regions such as signal peptide, extracellular region, transmembrane region and intracellular region. The molecular weight ranges from 60 to 100kDa and is rich in protein. Contains N- and O-glycosylation sites. VZV structural protein gE is the most abundantly expressed on the virus surface and plays an important role in virus transmission. It is also one of the main antigens that induces humoral and cellular immunity in the host. In 1974, Japan developed the Oka strain vaccine, an attenuated VZV strain. Based on this, subunit vaccines using VZV surface gE as an antigen have recently emerged. As a structural protein on the surface of varicella-zoster, gE is highly conserved and has become the focus of VZV vaccine development in recent years. Because of the complete structure of the gE protein, it can attach to the surface of the virus and form a target for cellular immunity. It can also complete the expression of the extracellular region through the guidance of signal peptides, thereby inducing a humoral immune response. In recent years, the research and development of VZV vaccines has mainly focused on the expression levels of gE protein in different expression systems and the operational technical routes.
Alternative Names
VZV gE protein
Varicella-zoster virus glycoprotein E
VZV glycoprotein E antigen
VZV gE antigen
Recombinant gE protein
VZV envelope glycoprotein E
VZV gE glycoprotein
References
- 1. Zerboni L, et al., Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol. 2014, 12(3):197-210.
References
Effects of Varicella-Zoster Virus Glycoprotein E Carboxyl-Terminal Mutation on mRNA Vaccine Efficacy
Vaccines (Basel)
Authors: Cao H, Wang Y, Luan N, et al.
Abstract
Glycoprotein E (gE) is one of the most abundant glycoproteins in varicella-zoster virus and plays pivotal roles in virus replication and transmission between ganglia cells. Its extracellular domain has been successfully used as an antigen in subunit zoster vaccines. The intracellular C-terminal domain was reported to be decisive for gE trafficking between the endoplasmic reticulum, trans-Golgi network and endosomes and could influence virus spread and virus titers. Considering that the trafficking and distribution of mRNA vaccine-translated gE may be different from those of gE translated against the background of the viral genome (e.g., most gE in virus-infected cells exists as heterodimers with another glycoprotein, gI,), which may influence the immunogenicity of gE-based mRNA vaccines, we compared the humoral and cellular immunity induced by LNP-encapsulated mRNA sequences encoding the whole length of gE, the extracellular domain of gE and a C-terminal double mutant of gE (mutant Y569A with original motif AYRV, which targets gE to TGN, and mutants S593A, S595A, T596A and T598A with the original motif SSTT) that were reported to enhance virus spread and elevate virus titers. The results showed that while the humoral and cellular immunity induced by all of the mRNA vaccines was comparable to or better than that induced by the AS01B-adjuvanted subunit vaccines, the C-terminal double mutant of gE showed stable advantages in all of the indicators tested, including gE-specific IgG titers and T cell responses, and could be adopted as a candidate for both safer varicella vaccines and effective zoster vaccines.
Regulation of the ORF61 Promoter and ORF61 Functions in Varicella-Zoster Virus Replication and Pathogenesis
JOURNAL OF VIROLOGY
Authors: Wang, Li; Sommer, Marvin; Rajamani, Jaya; Arvin, Ann M.
Abstract
Varicella-zoster virus (VZV) open reading frame 61 (ORF61) encodes a protein that transactivates viral and cellular promoters in transient-transfection assays and is the ortholog of herpes simplex virus ICP0. In this report, we mapped the ORF61 promoter and investigated its regulation by viral and cellular proteins in transient-expression experiments and by mutagenesis of the VZV genome (parent Oka strain). The 5' boundary of the minimal ORF61 promoter required for IE62 transactivation was mapped to position -95 relative to the mRNA start site, and three noncanonical GT-rich Sp1-binding sites were documented to occur within the region comprising positions -95 to -45. Contributions of the three Sp1-binding-site motifs, designated Sp1a, Sp1b, and Sp1c, to ORF61 expression and viral replication were varied despite their similar sequences. Two sites, Sp1a and Sp1c, functioned synergistically. When both sites were mutated in the pOka genome to produce pOka-61pro Delta Sp1ac, the mutant virus expressed significantly less ORF61 protein. Using this mutant to investigate ORF61 functions resulted in reductions in the expression levels of IE proteins, viral kinases ORF47 and ORF66, and the major glycoprotein gE, with the most impact on gE. Virion morphogenesis appeared to be intact despite minimal ORF61 expression. Pretreating melanoma cells with sodium butyrate enhanced titers of pOka-61pro Delta Sp1ac but not pOka, suggesting that ORF61 has a role in histone deacetylase inhibition. Growth of pOka-61pro Delta Sp1ac was impaired in SCIDhu skin xenografts, indicating that the regulation of the ORF61 promoter by Sp1 family proteins is important for ORF61 expression in vivo and that ORF61 contributes to VZV virulence at skin sites of replication.
Herpes Zoster DNA Vaccines with IL-7 and IL-33 Molecular Adjuvants Elicit Protective T Cell Immunity
IMMUNE NETWORK
Authors: Kim, A. Reum; Park, Junsik; Kim, Jong Hoon; Kwak, Jeong-Eun; Cho, Youngran; Lee, Hyojin; Jeong, Moonsup; Park, Su-Hyung; Shin, Eui-Cheol
Abstract
Herpes zoster (HZ), or shingles, is caused by the reactivation of latent varicella-zoster virus (VZV) from the sensory ganglia when VZV-specific T-cell immunity is decreased because of aging or immunosuppression. In the present study, we developed HZ DNA vaccine candidates encoding VZV proteins and cytokine adjuvants, such as IL-7 and IL-33. We immunized C57BL/6 mice with DNA plasmids encoding VZV glycoprotein E (gE), immediate early (IE) 63, or IE62 proteins and found that robust VZV protein-specific T-cell responses were elicited by HZ DNA vaccination. Co-administration of DNA plasmids encoding IL-7 or IL-33 in HZ DNA vaccination significantly enhanced the magnitude of VZV proteinspecific T-cell responses. Protective immunity elicited by HZ DNA vaccination was proven by challenge experiments with a surrogate virus, vaccinia virus expressing gE (VV-gE). A single dose of HZ DNA vaccine strongly boosted gE-specific T-cell responses in mice with a history of previous infection by VV-gE. Thus, HZ DNA vaccines with IL-7 and IL-33 adjuvants strongly elicit protective immunity.
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