Recombinant Glycoprotein E of Varicella Zoster Virus Contains Glycan-Peptide Motifs That Modulate B Cell Epitopes into Discrete Immunological Signatures

A recombinant subunit vaccine (Shingrix®) was recently licensed for use against herpes zoster. This vaccine is based on glycoprotein E (gE) of varicella zoster virus (VZV), the most abundantly expressed protein of VZV, harboring sites for N- and O-linked glycosylation. The subunit vaccine elicits stronger virus-specific CD4+ T cell response as well as antibody B cell response to gE, compared to the currently used live attenuated vaccine (Zostavax®). This situation is at variance with the current notion since a live vaccine, causing an active virus infection, should be far more efficient than a subunit vaccine based on only one single viral glycoprotein. We previously found gE to be heavily glycosylated, not least by numerous clustered O-linked glycans, when it was produced in human fibroblasts. However, in contrast to Zostavax®, which is produced in fibroblasts, the recombinant gE of Shingrix® is expressed in Chinese hamster ovary (CHO) cells. Hence, the glycan occupancy and glycan structures of gE may differ considerably between the two vaccine types. Here, we aimed at (i) defining the glycan structures and positions of recombinant gE and (ii) identifying possible features of the recombinant gE O-glycosylation pattern contributing to the vaccine efficacy of Shingrix®. Firstly, recombinant gE produced in CHO cells (“Shingrix situation”) is more scarcely decorated by O-linked glycans than gE from human fibroblasts (“Zostavax situation”), with respect to glycan site occupancy. Secondly, screening of immunodominant B cell epitopes of gE, using a synthetic peptide library against serum samples from VZV-seropositive individuals, revealed that the O-linked glycan signature promoted binding of IgG antibodies via a decreased number of interfering O-linked glycans, but also via specific O-linked glycans enhancing antibody binding. These findings may, in part, explain the higher protective efficacy of Shingrix®, and can also be of relevance for development of subunit vaccines to other enveloped viruses.

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B-cell epitopes of varicella-zoster virus glycoprotein II

Archives of Virology ◽

10.1007/bf01718644 ◽

1996 ◽

Vol 141 (12) ◽

pp. 2465-2469 ◽

Cited By ~ 2

Author(s):

A. Kjartansdóttir ◽

E. Lycke ◽

S. R. Norrby

Keyword(s):

B Cell ◽

Varicella Zoster Virus ◽

B Cell Epitopes ◽

Varicella Zoster ◽

Virus Glycoprotein

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Identification of Immunodominant Regions and Linear B Cell Epitopes of the gE Envelope Protein of Varicella-Zoster Virus

Virology ◽

10.1006/viro.1995.0064 ◽

1995 ◽

Vol 214 (2) ◽

pp. 531-540 ◽

Cited By ~ 21

Author(s):

WENDY J. FOWLER ◽

MERCEDES GARCIA-VALCARCEL ◽

MICHELE S. HILL-PERKINS ◽

GARY MURPHY ◽

DAVID R. HARPER ◽

...

Keyword(s):

B Cell ◽

Varicella Zoster Virus ◽

Envelope Protein ◽

B Cell Epitopes ◽

Varicella Zoster ◽

Linear B

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Culture media optimization for Chinese hamster ovary cell growth and expression of recombinant varicella-zoster virus glycoprotein E

Cytotechnology ◽

10.1007/s10616-021-00468-1 ◽

2021 ◽

Author(s):

Kwang Sung Kim ◽

Shin Ae Park ◽

Seo Ri Wui ◽

Ara Ko ◽

Na Gyong Lee

Keyword(s):

Cell Growth ◽

Varicella Zoster Virus ◽

Chinese Hamster Ovary Cell ◽

Chinese Hamster Ovary ◽

Culture Media ◽

Chinese Hamster ◽

Ovary Cell ◽

Media Optimization ◽

Glycoprotein E ◽

Varicella Zoster

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Antigenic Variation of Varicella Zoster Virus Fc Receptor gE: Loss of a Major B Cell Epitope in the Ectodomain

Virology ◽

10.1006/viro.1998.9313 ◽

1998 ◽

Vol 249 (1) ◽

pp. 21-31 ◽

Cited By ~ 57

Author(s):

Richard A. Santos ◽

Jorge A. Padilla ◽

Christopher Hatfield ◽

Charles Grose

Keyword(s):

B Cell ◽

Varicella Zoster Virus ◽

Antigenic Variation ◽

Cell Epitope ◽

Fc Receptor ◽

Varicella Zoster ◽

B Cell Epitope

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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 ◽

10.1093/infdis/jis497 ◽

2012 ◽

Vol 206 (8) ◽

pp. 1280-1290 ◽

Cited By ~ 100

Author(s):

Isabel Leroux-Roels ◽

Geert Leroux-Roels ◽

Frédéric Clement ◽

Pierre Vandepapelière ◽

Ventzislav Vassilev ◽

...

Keyword(s):

Older Adults ◽

Clinical Trial ◽

Subunit Vaccine ◽

Vaccine Candidate ◽

Phase 1 ◽

Glycoprotein E ◽

Varicella Zoster

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The Amino Terminus of Varicella-Zoster Virus (VZV) Glycoprotein E Is Required for Binding to Insulin-Degrading Enzyme, a VZV Receptor

Journal of Virology ◽

10.1128/jvi.00286-07 ◽

2007 ◽

Vol 81 (16) ◽

pp. 8525-8532 ◽

Cited By ~ 20

Author(s):

Qingxue Li ◽

Tammy Krogmann ◽

Mir A. Ali ◽

Wei-Jen Tang ◽

Jeffrey I. Cohen

Keyword(s):

Amino Acids ◽

Varicella Zoster Virus ◽

Catalytic Domain ◽

Amino Terminus ◽

Dependent Manner ◽

Insulin Degrading Enzyme ◽

Concentration Dependent Manner ◽

Glycoprotein E ◽

Degrading Enzyme ◽

Varicella Zoster

ABSTRACT Varicella-zoster virus (VZV) glycoprotein E (gE) is required for VZV infection. Although gE is well conserved among alphaherpesviruses, the amino terminus of VZV gE is unique. Previously, we showed that gE interacts with insulin-degrading enzyme (IDE) and facilitates VZV infection and cell-to-cell spread of the virus. Here we define the region of VZV gE required to bind IDE. Deletion of amino acids 32 to 71 of gE, located immediately after the predicted signal peptide, resulted in loss of the ability of gE to bind IDE. A synthetic peptide corresponding to amino acids 24 to 50 of gE blocked its interaction with IDE in a concentration-dependent manner. However, a chimeric gE in which amino acids 1 to 71 of VZV gE were fused to amino acids 30 to 545 of herpes simplex virus type 2 gE did not show an increased level of binding to IDE compared with that of full-length HSV gE. Thus, amino acids 24 to 71 of gE are required for IDE binding, and the secondary structure of gE is critical for the interaction. VZV gE also forms a heterodimer with glycoprotein gI. Deletion of amino acids 163 to 208 of gE severely reduced its ability to form a complex with gI. The amino portion of IDE, as well an IDE mutant in the catalytic domain of the protein, bound to gE. Therefore, distinct motifs of VZV gE are important for binding to IDE or to gI.

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T-cell response against varicella-zoster virus in fingolimod-treated MS patients

Neurology ◽

10.1212/wnl.0b013e31829a3311 ◽

2013 ◽

Vol 81 (2) ◽

pp. 174-181 ◽

Cited By ~ 44

Author(s):

M. E. Ricklin ◽

J. Lorscheider ◽

A. Waschbisch ◽

C. Paroz ◽

S. K. Mehta ◽

...

Keyword(s):

T Cell ◽

Varicella Zoster Virus ◽

Cell Response ◽

T Cell Response ◽

Varicella Zoster

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Functions of the C-Terminal Domain of Varicella-Zoster Virus Glycoprotein E in Viral Replication In Vitro and Skin and T-Cell Tropism In Vivo

Journal of Virology ◽

10.1128/jvi.78.22.12406-12415.2004 ◽

2004 ◽

Vol 78 (22) ◽

pp. 12406-12415 ◽

Cited By ~ 34

Author(s):

Jennifer Moffat ◽

Chengjun Mo ◽

Jason J. Cheng ◽

Marvin Sommer ◽

Leigh Zerboni ◽

...

Keyword(s):

T Cell ◽

Viral Replication ◽

Varicella Zoster Virus ◽

Point Mutations ◽

Glycoprotein E ◽

Varicella Zoster ◽

Terminal Domain ◽

C Terminus

ABSTRACT Varicella-zoster virus (VZV) glycoprotein E (gE) is essential for VZV replication. To further analyze the functions of gE in VZV replication, a full deletion and point mutations were made in the 62-amino-acid (aa) C-terminal domain. Targeted mutations were introduced in YAGL (aa 582 to 585), which mediates gE endocytosis, AYRV (aa 568 to 571), which targets gE to the trans-Golgi network (TGN), and SSTT, an “acid cluster” comprising a phosphorylation motif (aa 588 to 601). Substitutions Y582G in YAGL, Y569A in AYRV, and S593A, S595A, T596A, and T598A in SSTT were introduced into the viral genome by using VZV cosmids. These experiments demonstrated a hierarchy in the contributions of these C-terminal motifs to VZV replication and virulence. Deletion of the gE C terminus and mutation of YAGL were lethal for VZV replication in vitro. Mutations of AYRV and SSTT were compatible with recovery of VZV, but the AYRV mutation resulted in rapid virus spread in vitro and the SSTT mutation resulted in higher virus titers than were observed for the parental rOka strain. When the rOka-gE-AYRV and rOka-gE-SSTT mutants were evaluated in skin and T-cell xenografts in SCIDhu mice, interference with TGN targeting was associated with substantial attenuation, especially in skin, whereas the SSTT mutation did not alter VZV infectivity in vivo. These results provide the first information about how targeted mutations of this essential VZV glycoprotein affect viral replication in vitro and VZV virulence in dermal and epidermal cells and T cells within intact tissue microenvironments in vivo.

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