The multipartite system that mediates entry of herpes simplex virus into the cell

  title={The multipartite system that mediates entry of herpes simplex virus into the cell},
  author={Gabriella Campadelli-Fiume and Michele Amasio and Elisa Avitabile and Arianna Cerretani and Cristina Forghieri and Tatiana Gianni and Laura Menotti},
  journal={Reviews in Medical Virology},
The multipartite entry‐fusion system of herpes simplex virus is made of a quartet of glycoproteins—gD, gB, gH·gL—and three alternative gD receptors, herpesvirus entry mediator (HVEM), nectin1 and modified sites on heparan sulphate. This multipartite system recapitulates the basic steps of virus—cell fusion, i.e. receptor recognition, triggering of fusion and fusion execution. Specifically, in addition to serving as the receptor‐binding glycoprotein, gD triggers fusion through a specialised… 

Herpes Simplex Virus gD Forms Distinct Complexes with Fusion Executors gB and gH/gL in Part through the C-terminal Profusion Domain*

To understand how the four glycoproteins cross-talk to each other, the results indicate that gD carries composite-independent binding sites for gB and gH/gL, both of which are partly located in the profusion domain.

The Engineering of a Novel Ligand in gH Confers to HSV an Expanded Tropism Independent of gD Activation by Its Receptors

GH represents an additional tool for the design of fully-virulent oncolytic-HSVs retargeted to cancer receptors and detargeted from gD receptors, which do not require the gD-dependent activation, and replicate and kill cells at high efficiency.

Insertion of a ligand to HER2 in gB retargets HSV tropism and obviates the need for activation of the other entry glycoproteins

This study shows that gB can be modified and become the major determinant of HSV tropism; the chimeric gBHER2 bypasses the requirement for receptor-mediated activation of other essential entry glycoproteins.

HSV Glycoprotein B Fusion Loop Architecture and Mechanisms of Fusion Inhibition

The mutagenic analysis of the putative HSV gB fusion loops supports the concept that gB functions as a fusion protein and that its two fusion loops act in much the same way as do the fusion loops of VSV G or the class II fusion proteins.

αvβ6- and αvβ8-Integrins Serve As Interchangeable Receptors for HSV gH/gL to Promote Endocytosis and Activation of Membrane Fusion

It is proposed that placing the gH/gL activation under the integrin trigger point enables HSV to synchronize virion endocytosis with the cascade of glycoprotein activation that culminates in execution of fusion.

Reevaluating Herpes Simplex Virus Hemifusion (cid:1)

To verify that the hemifusion assay was capable of detecting hemifusions, glycosylphosphatidylinositol (GPI)-linked hemagglutinin (HA) was used, a variant of the influenza virus fusion protein, HA, known to stall the fusion process before productive fusion pores are formed.

Intracellular Trafficking and Maturation of Herpes Simplex Virus Type 1 gB and Virus Egress Require Functional Biogenesis of Multivesicular Bodies

The view that the sorting of gB to MVB membranes may represent a critical step in HSV envelopment and egress and that modified MVBs membranes constitute a platform for HSV cytoplasmic envelopment or that MVB components are recruited to the site(s) of envelopment is supported.

Dissociation of HSV gL from gH by αvβ6- or αvβ8-integrin promotes gH activation and virus entry

It is proposed that gL dissociation from gH/gL is part of the activation of HSV glycoproteins, critical for HSV entry; and gL is a functional inhibitor of gH and maintains gH in an inhibited form until receptor-bound gD and integrins signal to gH /gL.

Caractérisation de la migration du virus Herpès simplex de type 1 (HSV-1) par protéomique

The results revealed that, unlike ICP0 and ICP4 proteins, UL7 and UL23 can be released from the capsid in the presence of salts, and the potential incorporation of 49 cellular proteins was revealed.



Potential Nectin-1 Binding Site on Herpes Simplex Virus Glycoprotein D

The results suggest that this region of gD is important for nectin-1 interaction and is distinct from but partially overlaps the site of HVEM binding.

Structure of unliganded HSV gD reveals a mechanism for receptor‐mediated activation of virus entry

It is proposed that a controlled displacement of the gD C‐terminus upon receptor binding is an essential feature of HSV entry, ensuring the timely activation of membrane fusion.

The pro-fusion domain of herpes simplex virus glycoprotein D (gD) interacts with the gD N terminus and is displaced by soluble forms of viral receptors.

This work proposes that gD adopts a "closed" conformation before receptor binding, gD modifies its conformation and the N and C termini are released from reciprocal interactions and enabled to trigger fusion, and shows that PFD bound soluble forms of gD, truncated at residue 260 (gD260t) or downstream.

The soluble ectodomain of herpes simplex virus gD contains a membrane-proximal pro-fusion domain and suffices to mediate virus entry.

It is reported that the gD ectodomain in soluble form was sufficient to rescue the infectivity of a gD-null HSV mutant, indicating that gD does not need to be anchored to the virion envelope to mediate entry.

The novel receptors that mediate the entry of herpes simplex viruses and animal alphaherpesviruses into cells

The first example of a mediator of HSV entry independent of a detectable interaction with gD is provided, and the human nectin1α‐δ is the promiscuous species non‐specific receptor activity towards the animal alphaherpesviruses, pseudorabies virus and bovine herpesvirus 1 (BHV‐1).

Separation of receptor-binding and profusogenic domains of glycoprotein D of herpes simplex virus 1 into distinct interacting proteins

Results indicate that codons 61-residue glycoprotein D do not encode executable functions required for viral entry into cells and suggest that the receptor-binding ligand must interact with but need not alter the structure of the residual portion of gD to effect virus entry.

Entry of alphaherpesviruses into the cell

Herpes simplex virus (HSV) represents the most comprehensive example of virus-receptor interaction in the Herpesviridae family, and the prototype virus encoding multipartite entry genes. Whereas

Structure-Based Mutagenesis of Herpes Simplex Virus Glycoprotein D Defines Three Critical Regions at the gD-HveA/HVEM Binding Interface

Of the 35 gD and HveA contact residues that comprise the gD-HveA interface, only a handful are critical for complex formation, and this study shows that one gD residue that contacts CRD2 contributes to Hve a binding.

Use of herpes simplex virus and pseudorabies virus chimeric glycoprotein D molecules to identify regions critical for membrane fusion.

It is shown here that PRV gD, when coexpressed with HSV gB, gH, and gL, cannot substitute for HSVs gD in inducing fusion with target cells expressing nectin-1, and that chimeric gD molecules composed of HSV and PRV sequences can substitute, provided the first 285 aa are from HSv gD.