A novel herpes simplex virus glycoprotein, gL, forms a complex with glycoprotein H (gH) and affects normal folding and surface expression of gH

Hutchinson, Lloyd; Browne, Helena; Wargent, V; Davis-Poynter, Nicholas; Primorac, S.; Goldsmith, Kimberley; Minson, A. C.; Johnson, David C.

doi:10.1128/jvi.66.4.2240-2250.1992

Cited by 305 publications

(164 citation statements)

References 45 publications

Supporting

Mentioning

155

Contrasting

Order By: Relevance

“…The Western blot signal for gL was also low with anti-gH/gL PAb R137. Yet gL is expected to be present in equimolar amounts with gH because gH needs gL for proper folding (31,32) and in its absence is not expressed on cell surface (33) or incorporated into virions (12). To verify the presence of gL in VSV⌬G-BHLD virions, another, comparable VSV⌬G-BHLD preparation was tested with an anti-gL MAb, showing that gL is present in purified VSV⌬G-BHLD despite the low signal from the R137 blot (Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Vesicular Stomatitis Virus Pseudotypes Bearing Essential Entry Glycoproteins gB, gD, gH, and gL of Herpes Simplex Virus 1

Rogalin

Heldwein

2016

J Virol

View full text Add to dashboard Cite

Herpes simplex viruses (HSVs) are unusual in that unlike most enveloped viruses, they require at least four entry glycoproteins, gB, gD, gH, and gL, for entry into target cells in addition to a cellular receptor for gD. The dissection of the herpes simplex virus 1 (HSV-1) entry mechanism is complicated by the presence of more than a dozen proteins on the viral envelope. To investigate HSV-1 entry requirements in a simplified system, we generated vesicular stomatitis virus (VSV) virions pseudotyped with HSV-1 essential entry glycoproteins gB, gD, gH, and gL but lacking the native VSV fusogen G. These virions, referred to here as VSV⌬G-BHLD virions, infected a cell line expressing a gD receptor, demonstrating for the first time that the four essential entry glycoproteins of HSV-1 are not only required but also sufficient for cell entry. To our knowledge, this is the first time the VSV pseudotyping system has been successfully extended beyond two proteins. Entry of pseudotyped virions required a gD receptor and was inhibited by HSV-1 specific anti-gB or anti-gH/gL neutralizing antibodies, which suggests that membrane fusion during the entry of the pseudotyped virions shares common requirements with the membrane fusion involved in HSV-1 entry and HSV-1-mediated syncytium formation. The HSV pseudotyping system established in this study presents a novel tool for systematic exploration of the HSV entry and membrane fusion mechanisms. IMPORTANCEHerpes simplex viruses (HSVs) are human pathogens that can cause cold sores, genital herpes, and blindness. No vaccines or preventatives are available. HSV entry into cells-a prerequisite for a successful infection-is a complex process that involves multiple viral and host proteins and occurs by different routes. Detailed mechanistic knowledge of the HSV entry is important for understanding its pathogenesis and would benefit antiviral and vaccine development, yet the presence of more than a dozen proteins on the viral envelope complicates the dissection of the HSV entry mechanisms. In this study, we generated heterologous virions displaying the four essential entry proteins of HSV-1 and showed that they are capable of cell entry and, like HSV-1, require all four entry glycoproteins along with a gD receptor. This HSV pseudotyping system pioneered in this work opens doors for future systematic exploration of the herpesvirus entry mechanisms.T o enter living cells to replicate, viruses must overcome the barrier of the cellular membrane. Enveloped viruses accomplish this task by facilitating the merger of their envelope with a target cell membrane, during which capsids are delivered into the cytosol and infection ensues. Entry is initiated by binding of a virus to an appropriate receptor on the surface of the host cell and is catalyzed by a virus-encoded membrane fusogen. In most enveloped viruses, the receptor binding and the fusogenic functions are executed by a single protein (1).Herpesviruses are double-stranded DNA, enveloped viruses with intricate envelopes that contain...

show abstract

Section: Resultsmentioning

confidence: 99%

Characterization of Vesicular Stomatitis Virus Pseudotypes Bearing Essential Entry Glycoproteins gB, gD, gH, and gL of Herpes Simplex Virus 1

Rogalin

Heldwein

2016

J Virol

View full text Add to dashboard Cite

show abstract

“…Three of these glycoproteins are membrane spanning (gB, gD and gH), whereas gL is a soluble glycoprotein expressed at the virion and cell surface only in a heterodimer with gH. Besides, HSV-1 gH is not trafficked to the cell surface in the absence of gL [24].…”

Section: Introductionmentioning

confidence: 99%

Peptides containing membrane-interacting motifs inhibit herpes simplex virus type 1 infectivity

et al. 2008

View full text Add to dashboard Cite

Herpes simplex virus (HSV) membrane fusion represents an attractive target for anti-HSV therapy. To investigate the structural basis of HSV membrane fusion and identify new targets for inhibition, we have investigated the different membranotropic domains of HSV-1 gH envelope glycoprotein. We observed that fusion peptides when added exogenously are able to inhibit viral fusion likely by intercalating with viral fusion peptides upon adopting functional structure in membranes. Interestingly, peptides analogous to the predicted HSV-1 gH loop region inhibited viral plaque formation more significantly. Their inhibitory effect appears to be a consequence of their ability to partition into membranes and aggregate within them. Circular dichroism spectra showed that peptides self-associate in aqueous and lipidic solutions, therefore the inhibition of viral entry may occur via peptides association with their counterpart on wild-type gH. The antiviral activity of HSV-1 peptides tested provides an attractive basis for the development of new fusion peptide inhibitors corresponding to regions outside the fusion protein heptad repeat regions.

show abstract

“…Active peptide details. Inhibitory gH peptides at 150 μM with the respective sequences, % of inhibition and protein position and the respective IC 50 and IC 90 . The highest peptide concentration used is 250 μM; therefore, Graphpad Prism results above this concentration for IC 90 univ-paris-diderot.fr/) databases, respectively (Figures 3 and 4).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, peptides matching a number of regions of the gH ectodomain have been shown to interact with membranes and proposed to play a role in the fusion process, probably through regulation of gB activity and/or direct membrane interactions at the fusion site [39][40][41][42][43][44][45][46][47]. In HSV-infected cells and on mature virions, gH and gL are always found together as an heterodimer, in a stable 1 : 1 complex [33,48] and rely on one another for proper folding, post-translational processing and transport to the cell and virion surface [49][50][51][52]. HSV-1 gH is a 838-residue type 1 membrane glycoprotein.…”

Section: Introductionmentioning

confidence: 99%

Infectivity inhibition by overlapping synthetic peptides derived from the gH/gL heterodimer of herpes simplex virus type 1

Franci

Falanga

Zannella

et al. 2017

Journal of Peptide Science

View full text Add to dashboard Cite

Herpes simplex virus (HSV) is a human pathogen that infects epithelial cells. The cutaneous lesions, caused by the virus, spread to the nervous system creating several complications. Fusion of host membranes with the viral envelope is mandatory and mediated by a group of glycoproteins conserved in all Herpesviridae subfamilies, such as the glycoproteins B (gB), H (gH), L (gL) and D (gD). We investigated the inhibitory activity mediated by synthetic overlapping peptides spanning the entire ectodomains of gH and gL glycoproteins. We have performed a brute analysis of the complete gH/gL heterodimer in order to explore the inhibitory activity of peptides modelled on these glycoproteins against HSV-1 infection. Twenty-four of the gH peptides at a concentration of 150 μM reached the 50% of inhibition cut-off. Interestingly, they are mainly located in the gH carboxy-terminal domain. None of the gL peptides had a clear inhibiting effect. No peptide toxicity was observed by lactate dehydrogenase assay at the concentrations used in our experimental conditions. HSV-1 therapy is based on acyclovir treatment, but some resistant strains are emerging. In this scenario, innovative approaches for HSV-1 treatment are necessary. Our data support the direct involvement of the described domains in the process of virus penetration; therefore, these results are of relevance to the potential development of novel therapeutic compounds to prevent HSV-1 infections. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

show abstract

A novel herpes simplex virus glycoprotein, gL, forms a complex with glycoprotein H (gH) and affects normal folding and surface expression of gH

Cited by 305 publications

References 45 publications

Characterization of Vesicular Stomatitis Virus Pseudotypes Bearing Essential Entry Glycoproteins gB, gD, gH, and gL of Herpes Simplex Virus 1

Characterization of Vesicular Stomatitis Virus Pseudotypes Bearing Essential Entry Glycoproteins gB, gD, gH, and gL of Herpes Simplex Virus 1

Peptides containing membrane-interacting motifs inhibit herpes simplex virus type 1 infectivity

Infectivity inhibition by overlapping synthetic peptides derived from the gH/gL heterodimer of herpes simplex virus type 1

Contact Info

Product

Resources

About