The COMPLEXity in herpesvirus entry

Abstract

Enveloped viruses have evolved diverse transmembrane proteins and protein complexes to enable host cell entry by regulating and activating membrane fusion in a target cell-specific manner. In general terms, the entry process requires a receptor binding step, an activation step and a membrane fusion step, which can be encoded within a single viral protein or distributed among multiple viral proteins. HIV and influenza virus, for example, encode all of these functions in a single trimeric glycoprotein, HIV env or influenza virus hemagglutinin (HA). In contrast, herpesviruses have the host receptor binding, activation and fusogenic roles distributed among multiple envelope glycoproteins (ranging from three to six), which must coordinate their functions at the site of fusion. Despite the apparent complexity in the number of viral entry proteins, herpesvirus entry is fundamentally built around two core glycoprotein entities: the gHgL complex, which appears to act as an 'activator' of entry, and the gB protein, which is thought to act as the membrane 'fusogen'. Both are required for all herpesvirus fusion and entry. In many herpesviruses, gHgL either binds host receptors directly or assembles into larger complexes with additional viral proteins that bind host receptors, conferring specificity to the cells that are targeted for infection. These gHgL entry complexes (ECs) are centrally important to activating gB-mediated membrane fusion and establishing viral tropism, forming membrane bridging intermediates before gB triggering. Here we review recent structural and functional studies of Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) gHgL complexes that provide a framework for understanding the role of gHgL in herpesvirus entry. Furthermore, a recently determined EM model of Herpes Simplex virus (HSV) gB embedded in exosomes highlights how gB conformational changes may promote viral and cellular membrane fusion.

Figure 1.. Herpesvirus entry glycoproteins gHgL and gB crystal structures.

Known protein data bank (PDB) structures of (a) gHgL and (b) gB are summarized. Left of panel (b) also shows comparisons to the other class III fusion protein, VSV G, whose structures in both pre-fusion and post-fusion states are shown in the same color scheme for comparison. It must be noted that VSV G is much smaller than herpesvirus gB and does not have a gHgL equivalent. The individual glycoprotein structures provide a basis for understanding interactions in larger complexes as visualized by electron microscopy (EM).

Figure 2.. EM and crystal structures of EBV and CMV entry complexes.

(a) The crystal structure of the EBV gHgL/gp42 complex (PDB ID: 5T1D) [22], showing interactions of the extended gp42 N-terminal domain and location of the HLA-binding gp42 C-terminal domain. (b) CMV gHgL forms gHgL/gO trimers and gHgL/UL128/UL130/UL131 Pentamers through its N-terminal domain, as visualized by negative stain EM [17]. (c) EM structure of EBV gHgL/gp42 in complex with HLA receptor [22,41]. (d) The EM structure of the CMV gHgL/gO trimer in complex with PDGFRα receptor model (EMD-3391) [23]. (e) A ‘pre-postfusion’ HSV-1 gB model derived from sub-tomogram averaging of intact gB on vesicles (EMD-3362) [42]. Figures adapted from original publications and public databanks as cited. Other structures were rendered in Chimera (UCSF) and MacPymol (Schrödinger LLC).

Figure 3.. Herpesvirus gHgL is a versatile entry glycoprotein.

Entry mediated by various gHgL entry complexes and the corresponding cell types infected are schematically shown for HSV, CMV and EBV.