The Role of HSV Glycoproteins in Mediating Cell Entry

Abstract

The successful entry of herpes simplex virus (HSV) into a cell is a complex process requiring the interaction of several surface viral glycoproteins with host cell receptors. These viral glycoproteins are currently thought to work sequentially to trigger fusogenic activity, but the process is complicated by the fact that each glycoprotein is known to interact with a range of target cell surface receptor molecules. The glycoproteins concerned are gB, gD, and gH/gL, with at least four host cell receptor molecules known to bind to gB and gD alone. Redundancy among gD receptors is also evident and binding to both the gB and gD receptors simultaneously is known to be required for successful membrane fusion. Receptor type and tissue distribution are commonly considered to define the extent of viral tropism and thus the magnitude of pathogenesis. Viral entry receptors are therefore attractive pharmaceutical target molecules for the prevention and/or treatment of viral infections. However, the large number of HSV glycoprotein receptors makes a comprehensive understanding of HSV pathogenesis in vivo difficult. Here we summarize our current understanding of the various HSV glycoprotein cell surface receptors, define their redundancy and binding specificity, and discuss the significance of these interactions for viral pathogenesis.

Simplexviruses successfully adapt to their host by fine-tuning immune responses

“…Specifically, we applied a branch-site test, which is well-suited to identify episodic positive selection -i.e., selection events that occurred on a specific branch of a phylogeny. Among core genes, we found evidence of episodic positive selection in three glycoproteins, namely gB, gM, and gH, all of which contribute to virus cell entry via membrane fusion (Arii and Kawaguchi, 2018;El Kasmi and Lippé, 2015). For gB and gH we found that some of the positively selected sites map to antigenic determinants, suggesting that the host adaptive immune response represents the underlying selective pressure.…”

Herpes Simplex Virus Oncolytic Immunovirotherapy: The Blossoming Branch of Multimodal Therapy

“…Second, both the interplay of viral and cellular components at the plasma membrane in initiating entry mechanisms, and the subsequent downstream signaling or intracellular events, have been investigated in depth at the biological, cellular, biochemical, molecular and structural levels. HSV has a set of four envelope glycoproteins essential for virus entry: gD (involved in specific receptor recognition and binding, and the triggering of the fusogenic signal to downstream effectors), gB (a class III fusogenic glycoprotein which executes fusion), and the heterodimer gH/gL (partnering gB to execute fusion, and lacking any similarity with any other fusion protein) [3,[107][108][109][110]. Recently, insights into additional gB domains spatially distant from the fusion loops have come from structural studies on the related alpha-herpesvirus varicella zoster virus (VZV) [111].…”

“…These glycoproteins exploit a wide array of natural receptors for target cell recognition and fusion execution. Thus HVEM/HveA, Nectin-1/HveC and 3-OS HS are receptors for gD, PILRα, MAG and NMHC-IIA and B are bound by gB, and gH/gL interact with integrins [5,109,[112][113][114][115]. This multipartite system allows the virus to penetrate via two different pathways-by fusion at the plasma membrane or by endocytosis [4,[116][117][118].…”

The Role of VP16 in the Life Cycle of Alphaherpesviruses

“…When nucleocapsid is transported to the secondary envelope loci that associate with the Golgi apparatus, VP16 cannot only bind to outer tegument proteins of the outer tegument-envelope complex but also directly bind to some glycoproteins of the complex (Figure 4). After contact with the glycoproteins, the produced nucleocapsids can effectively bud in vesicles to complete secondary envelopment; this is because the glycoproteins can identify specific receptors on the membrane and promote the penetration of virions (Arii and Kawaguchi, 2018;White et al, 2020).…”