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.
Highlights
Herpesviruses cause significant morbidity and mortality in humans and animals.There are more than 120 species of herpesvirus identified to date, including nine human herpesviruses [1]
This review focuses on the role of viral glycoproteins in membrane fusion events and the facilitation of virus entry and cell spread in mucosal/epithelial tissues and ganglionic neurons
The core fusion machinery of herpesviruses composed of glycoprotein B (gB), Glycoprotein D (gD), and glycoprotein H (gH)/Glycoprotein L (gL) is required for virus entry and virus-induced cell-cell fusion [35,40,81,126,127,128,129,130,131]
Summary
Herpesviruses cause significant morbidity and mortality in humans and animals. There are more than 120 species of herpesvirus identified to date, including nine human herpesviruses [1]. The family Herpesviridae include herpesviruses of mammals, birds, and reptiles. They are divided into three subfamilies, alpha, beta, or gamma, based on their genetic sequences and their biological properties [1,2]. Initial infection of mucosal epithelium with either HSV-1 or HSV-2 results in viral replication and shedding followed by immunopathogenesis resulting in cold sores, blisters, and genital lesions [13]. Famciclovir, vidarabine, penciclovir, and valacyclovir are often used to treat HSV infections. While these medications reduce the severity and frequency of the symptoms, they do not cure the infection. This review focuses on the role of viral glycoproteins in membrane fusion events and the facilitation of virus entry and cell spread in mucosal/epithelial tissues and ganglionic neurons
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