Two Sides to Every Story: Herpes Simplex Type-1 Viral Glycoproteins gB, gD, gH/gL, gK, and Cellular Receptors Function as Key Players in Membrane Fusion

Abstract

Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2) are prototypical alphaherpesviruses that are characterized by their unique properties to infect trigeminal and dorsal root ganglionic neurons, respectively, and establish life-long latent infections. These viruses initially infect mucosal epithelial tissues and subsequently spread to neurons. They are associated with a significant disease spectrum, including orofacial and ocular infections for HSV-1 and genital and neonatal infections for HSV-2. Viral glycoproteins within the virion envelope bind to specific cellular receptors to mediate virus entry into cells. This is achieved by the fusion of the viral envelope with the plasma membrane. Similarly, viral glycoproteins expressed on cell surfaces mediate cell-to-cell fusion and facilitate virus spread. An interactive complex of viral glycoproteins gB, gD/gH/gL, and gK and other proteins mediate these membrane fusion phenomena with glycoprotein B (gB), the principal membrane fusogen. The requirement for the virion to enter neuronal axons suggests that the heterodimeric protein complex of gK and membrane protein UL20, found only in alphaherpesviruses, constitute a critical determinant for neuronal entry. This hypothesis was substantiated by the observation that a small deletion in the amino terminus of gK prevents entry into neuronal axons while allowing entry into other cells via endocytosis. Cellular receptors and receptor-mediated signaling synergize with the viral membrane fusion machinery to facilitate virus entry and intercellular spread. Unraveling the underlying interactions among viral glycoproteins, envelope proteins, and cellular receptors will provide new innovative approaches for antiviral therapy against herpesviruses and other neurotropic viruses.

Primate Simplexviruses Differ in Tropism for Macaque Cells

“…The nature of the block to efficient infection of rhesus macaque cell lines with HSV1, HSV2 and CeHV2 remains to be elucidated. The entry of HSV1 into target cells is well studied [ 67 , 68 ] and encompasses the interaction of two glycoproteins, gD and gB, with multiple cellular receptors. Presently, little is known about the receptor usage of primate simplexviruses, although it has been shown that McHV1 can use human Nectin-1 but not the herpesvirus entry mediator or immunoglobulin-like type 2 receptor alpha for entry [ 69 , 70 ].…”

Cell Intrinsic Determinants of Alpha Herpesvirus Latency and Pathogenesis in the Nervous System

“…When bound to its receptor, gD undergoes conformational changes and activates the gH/gL heterodimer, which, in turn, activates gB, the principal fusogen that mediates the fusion of viral envelope and host cell membrane [66,67]. Upon entry, the viral nucleocapsid is transported to the nucleus via molecular motors.…”

HSV-1 Infection of Epithelial Dendritic Cells Is a Critical Strategy for Interfering with Antiviral Immunity

“…As an enveloped double-stranded linear DNA virus, HSV-1 has a genome approximately 150 kb in length and begins encoding following a linear time program under a tightly genomically regulated mechanism. The complicated genomic structure and transcriptional mechanism of HSV-1 allow it to express various structural and nonstructural proteins [ 5 ], including 12 glycoproteins (e.g., gD, gC, gE, and gG), which are expressed on the viral membrane and interact with different cellular receptors in various cells to achieve viral infection and spread in vivo [ 6 ]. Some virally encoded proteins can interact with molecules involved in the host immune system and inflammation and might interfere with their physiological roles in antiviral immunity [ 7 ].…”