Herpes simplex virus 1 glycoprotein D – host receptor interface (HSV-1 gD-host receptor interface)

The Herpes simplex virus 1 (HSV-1) glycoprotein D (gD) – host receptor interface is a pivotal molecular complex required for the virus to enter host cells. Glycoprotein D is an essential component of the HSV-1 envelope that functions as the primary attachment protein, binding to specific host cell surface receptors such as Herpesvirus Entry Mediator (HVEM), Nectin-1, Nectin-2, and 3-O-sulfated heparan sulfate [1, 3, 8]. This binding event triggers a critical conformational change in gD, which in turn activates the viral fusion machinery—comprising glycoproteins gH, gL, and gB—to facilitate the merger of the viral envelope with the host cell membrane [2, 4, 9]. Because different host tissues express different receptors, this interface is a primary determinant of viral tropism; for instance, Nectin-1 is the major receptor in neurons and epithelial cells, while HVEM is utilized in immune cells [5, 6, 11]. Targeting the gD-receptor interface represents a promising therapeutic strategy to block HSV-1 infection at the entry stage, potentially preventing the establishment of lifelong latency [7, 15, 18]. Current research focuses on developing monoclonal and bispecific antibodies, small molecules, and peptides that can disrupt these protein-protein interactions [12, 14, 19]. While Docosanol is currently the only marketed drug that inhibits viral fusion, it does so by modifying the host cell membrane rather than binding gD directly [7, 18]. Challenges in drug development for this target include the need to inhibit multiple receptor interfaces to ensure broad efficacy and the potential for off-target effects on the physiological signaling functions of host receptors like HVEM [1, 12, 17].

Other names

HSV-1 gD-receptor complexgD-HVEM interfacegD-Nectin-1 interfacegD-3-O-S-HS interfacegD-Nectin-2 interfaceHerpes simplex virus 1 glycoprotein D-host cell receptor interaction

Inhibition of viral entry by blocking the interaction between viral glycoprotein D and host receptors (HVEM, Nectin-1, or 3-O-S-HS), thereby preventing the conformational change in gD required to activate the viral fusion machinery [1, 3, 15, 19].