Evidence for a Role of the Membrane‐Proximal Region of Herpes Simplex Virus Type 1 Glycoprotein H in Membrane Fusion and Virus Inhibition

Abstract

We have identified a putative membrane-interacting domain preceding the transmembrane domain of the Herpes simplex virus type 1 (HSV-1) glycoprotein H (gH). Peptides derived from this region interact strongly with membranes and show a high tendency to partition at the interface. This region is predicted to bind at the membrane interface by adopting an alpha helical structure. Peptides representing either the HSV-1 gH pretransmembrane region or a scrambled control with a different hydrophobic profile at the point of interface have been studied. The peptides derived from this domain of gH induce the fusion of liposomal membranes, adopt helical conformations in membrane mimetic environments and are able to inhibit HSV-1 infectivity. The pretransmembrane region appears to be a common feature in viral fusion proteins of several virus families, and such a feature might be related to their fusogenic function. The identification of membrane-interacting regions capable of modifying the biophysical properties of phospholipid membranes lends weight to the view that such domains might function directly in the fusion process and could facilitate the future development of HSV-1 entry inhibitors.

The Presence of a Single N-terminal Histidine Residue Enhances the Fusogenic Properties of a Membranotropic Peptide Derived from Herpes Simplex Virus Type 1 Glycoprotein H

“…HSV-1 infection, similarly to other enveloped viruses, is achieved through fusion of the lipid bilayer of the viral envelope with a host cell membrane. The core fusion machinery of herpesviruses is well conserved and consists of the envelope glycoprotein B (gB) and the heterodimeric complex of gH/gL (15)(16)(17)(18)(19)(20). Although numerous studies have indicated that both gB and gH/gL exhibit varying degrees of fusogenic properties, the complete fusion is only achieved when the three proteins act together (21)(22)(23).…”

“…The three classes of viral membrane fusion proteins have been identified largely on the basis of the key structural features of the proteins, and a comprehensive treatment of this subject can be found in recent reviews (1, 30 -32). Although no structural data for HSV-1 gH or any of its homologues in other herpesviruses are available, gH has also been considered as a likely fusion effector (15,16,19,33).…”

Bimolecular complementation reveals that glycoproteins gB and gH/gL of herpes simplex virus interact with each other during cell fusion

“…Although the structure of gH/gL is unknown, indirect evidence suggests that this complex also has fusogenic properties. For example, synthetic peptides corresponding to several regions of HSV gH associate with membranes (9). Fusion-compromised HSV gH mutants have been isolated, emphasizing the importance of gH for fusion (10)(11)(12).…”

Analysis of a Membrane Interacting Region of Herpes Simplex Virus Type 1 Glycoprotein H

“…These regions, in conjunction with the membrane-proximal region (32) and the transmembrane anchor of the protein, seem to form a continuous tract of hydrophobic membrane interacting surfaces that could simultaneously destabilize viral and cellular opposing membranes at the point of fusion. According to recent studies, binding of gD to its receptor is followed by hemifusion carried out by gH/gL, and full fusion is completed by the interaction between gH/gL and gB that concurrently leads to complete bilayer merging (33,34).…”