Herpes simplex virus 2 envelope glycoproteins and virus–cell entry machinery (HSV-2 entry machinery)

The Herpes simplex virus 2 (HSV-2) envelope glycoproteins and virus–cell entry machinery comprise a sophisticated multi-protein complex essential for the infection of host cells. This machinery is primarily composed of four core glycoproteins: gD, which binds to host cell receptors such as nectin-1, nectin-2, and herpesvirus entry mediator (HVEM); the gH/gL heterodimer, which acts as a regulator; and gB, the primary membrane fusogen (MDPI Viruses 2021, 13(9), 1849; UniProt P89445). The entry process involves a sequential cascade where receptor binding by gD triggers conformational changes in gH/gL, which in turn activates gB to mediate fusion between the viral envelope and the host cell membrane (PNAS 2005, 102(15), 5564-5569). Because this machinery is indispensable for both initial infection and subsequent cell-to-cell spread, it represents a high-priority target for the development of entry-inhibiting antivirals and prophylactic or therapeutic vaccines (TandfOnline 2011, 11(1), 1-3). Current research focuses on monoclonal antibodies like UB-621 and HDIT101, as well as small molecules that can disrupt these protein-protein interactions or block receptor binding sites to prevent viral entry. These interventions aim to reduce the frequency of symptomatic outbreaks and viral shedding in patients with chronic genital herpes (ClinicalTrials.gov NCT04714060; Clin Transl Sci 2022, 15(10), 2366-2377). Additionally, targeting the entry machinery may help prevent neonatal transmission and reduce the risk of HIV co-infection. Despite its promise, the machinery's ability to facilitate cell-to-cell spread and the virus's establishment of latency in sensory neurons present significant therapeutic challenges.

Other names

HSV-2 core fusion machinerygB/gD/gH/gL complexHSV-2 entry glycoproteinsHSV-2 membrane fusion machinery

Inhibition of viral attachment to host receptors (HVEM, Nectin-1, Nectin-2, 3-O-sulfated heparan sulfate), prevention of conformational changes in the gB/gH/gL complex, and blockade of membrane fusion between the viral envelope and host cell membrane.