Overview of Varicella-Zoster Virus Glycoproteins gC, gH and gL

Grose, Charles; Carpenter, John E.; Jackson, Wallen; Duus, Karen

doi:10.1007/82_2009_4

Cited by 13 publications

(14 citation statements)

References 45 publications

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“…Similar to gB, gL and its interacting partner gH are highly conserved among herpesviruses. VZV gH and gL closely resemble their HSV orthologs (49). In general, both glycoproteins are major targets of virus-neutralizing antibodies, involved in inhibiting virus entry and infectivity (50).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

Roviš

Bailer

Pothineni

et al. 2013

J Virol

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i Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles. Due to the virus's restricted host and cell type tropism and the lack of tools for VZV proteomics, it is one of the least-characterized human herpesviruses. We generated 251 monoclonal antibodies (MAbs) against 59 of the 71 (83%) currently known unique VZV proteins to characterize VZV protein expression in vitro and in situ. Using this new set of MAbs, 44 viral proteins were detected by Western blotting (WB) and indirect immunofluorescence (IF); 13 were detected by WB only, and 2 were detected by IF only. A large proportion of viral proteins was analyzed for the first time in the context of virus infection. Our study revealed the subcellular localization of 46 proteins, 14 of which were analyzed in detail by confocal microscopy. Seven viral proteins were analyzed in time course experiments and showed a cascade-like temporal gene expression pattern similar to those of other herpesviruses. Furthermore, selected MAbs tested positive on human skin lesions by using immunohistochemistry, demonstrating the wide applicability of the MAb collection. Finally, a significant portion of the VZV-specific antibodies reacted with orthologs of simian varicella virus (SVV), thus enabling the systematic analysis of varicella in a nonhuman primate model system. In summary, this study provides insight into the potential function of numerous VZV proteins and novel tools to systematically study VZV and SVV pathogenesis. V aricella-zoster virus (VZV) belongs to the alphaherpesvirus subfamily and is the only member of the genus Varicellovirus that can infect humans (1, 2). Primary infection causes chickenpox and typically occurs in early childhood with a prominent, highly contagious vesicular rash (3). During primary infection, VZV establishes latency in sensory trigeminal and dorsal root ganglia. Reactivation from latency results in a secondary disease called herpes zoster (HZ), or shingles, that is more common in elderly people (4). HZ most frequently occurs in the thoracic or lumbar nerve segments and the distribution area of the trigeminal nerve, causing a painful rash in the corresponding dermatome. While the molecular mechanism for reactivation from latency is not well characterized, it is more frequent in immunocompromised patients (5). The most common sequela of HZ is postherpetic neuralgia (PHN). In addition, VZV reactivation can lead to zoster ophthalmicus, acute retinal necrosis, meningitis, and vasculopathy (6).The seroprevalence of VZV differs significantly between countries, but the majority of individuals are seropositive by the time of adolescence (7). While in otherwise healthy children and adolescents, primary VZV infection mostly resolves spontaneously without sequelae, severe symptoms may occur in immunocompromised people and during pregnancy (6). Vertical transmission of VZV during the first trimester causes congenital varicella syndrome (CVS), which is characterized by skin lesions, hypoplasia, low birth weight, and neurological dis...

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

Roviš

Bailer

Pothineni

et al. 2013

J Virol

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“…Similar to other herpesviruses, the fusion machinery core of VZV consists of gB, gH, and gL, which are expressed from open reading frame (ORF) 31, 37, and 60, respectively [13], [20]. While the crystal structure of the gB/gH-gL fusion complex has not been determined, X-ray crystallography of the individual glycoprotein components of other herpesviruses has provided insight into their function and roles in fusion.…”

Section: Introductionmentioning

confidence: 99%

“…Initially expressed as a 100 kilodalton (kDa) immature polypeptide, gH forms a heterodimer with gL, which is necessary for its maturation to a 118 or 130 kDa form [20], [27]. gH is processed in the Golgi apparatus and traffics to the cell surface, where it then undergoes endocytosis and returns to the trans-Golgi network (TGN) for incorporation into the virion envelope [28]–[32].…”

Section: Introductionmentioning

confidence: 99%

The Cytoplasmic Domain of Varicella-Zoster Virus Glycoprotein H Regulates Syncytia Formation and Skin Pathogenesis

2014

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The conserved herpesvirus fusion complex consists of glycoproteins gB, gH, and gL which is critical for virion envelope fusion with the cell membrane during entry. For Varicella Zoster Virus (VZV), the complex is necessary for cell-cell fusion and presumed to mediate entry. VZV causes syncytia formation via cell-cell fusion in skin and in sensory ganglia during VZV reactivation, leading to neuronal damage, a potential contributory factor for the debilitating condition of postherpetic neuralgia. The gH cytoplasmic domain (gHcyt) is linked to the regulation of gB/gH-gL-mediated cell fusion as demonstrated by increased cell fusion in vitro by an eight amino acid (aa834-841) truncation of the gHcyt. The gHcyt regulation was identified to be dependent on the physical presence of the domain, and not of specific motifs or biochemical properties as substitution of aa834-841 with V5, cMyc, and hydrophobic or hydrophilic sequences did not affect fusion. The importance of the gHcyt length was corroborated by stepwise deletions of aa834-841 causing incremental increases in cell fusion, independent of gH surface expression and endocytosis. Consistent with the fusion assay, truncating the gHcyt in the viral genome caused exaggerated syncytia formation and significant reduction in viral titers. Importantly, infection of human skin xenografts in SCID mice was severely impaired by the truncation while maintaining the gHcyt length with the V5 substitution preserved typical replication in vitro and in skin. A role for the gHcyt in modulating the functions of the gB cytoplasmic domain (gBcyt) is proposed as the gHcyt truncation substantially enhanced cell fusion in the presence of the gB[Y881F] mutation. The significant reduction in skin infection caused by hyperfusogenic mutations in either the gHcyt or gBcyt demonstrates that both domains are critical for regulating syncytia formation and failure to control cell fusion, rather than enhancing viral spread, is severely detrimental to VZV pathogenesis.

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“…VZV differs from other herpesviruses in that assembled virions typically remain highly cell-associated. The same viral glycoproteins that are predicted to mediate entry are expressed on cell membranes and induce fusion of infected and uninfected cells, producing syncytia and multinucleated polykaryocytes, which further contributes to virus spread 20–25 .…”

mentioning

confidence: 99%

Molecular mechanisms of varicella zoster virus pathogenesis

et al. 2014

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Varicella zoster virus (VZV) is the causative agent of varicella (chickenpox) and zoster (shingles). Investigating VZV pathogenesis is challenging as VZV is a human-specific virus and infection does not occur, or is highly restricted, in other species. However, the use of human tissue xenografts in mice with severe combined immunodeficiency (SCID) enables the analysis of VZV infection in differentiated human cells in their typical tissue microenvironment. Xenografts of human skin, dorsal root ganglia or foetal thymus that contains T cells can be infected with mutant viruses or in the presence of inhibitors of viral or cellular functions to assess the molecular mechanisms of VZV–host interactions. In this Review, we discuss how these models have improved our understanding of VZV pathogenesis.

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Overview of Varicella-Zoster Virus Glycoproteins gC, gH and gL

Cited by 13 publications

References 45 publications

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

The Cytoplasmic Domain of Varicella-Zoster Virus Glycoprotein H Regulates Syncytia Formation and Skin Pathogenesis

Molecular mechanisms of varicella zoster virus pathogenesis

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