Glycoproteins gE and gI Are Required for Efficient KIF1A-Dependent Anterograde Axonal Transport of Alphaherpesvirus Particles in Neurons

Kratchmarov, Radomir; Kramer, Tal; Greco, Todd M.; Taylor, Matthew P.; Ch’ng, Toh Hean; Cristea, Ileana M.; Enquist, Lynn W.

doi:10.1128/jvi.01317-13

Cited by 94 publications

(94 citation statements)

References 53 publications

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“…In addition, the role of the pUS9 acidic domain remains to be established precisely, given that this domain has been shown to be important for anterograde spread in a number of alphaherpesviruses (18)(19)(20). Finally, whether, and to what degree, the interaction of kinesin-3 and pUS9 identified in PrV (15,16) also is important for anterograde spread of HSV-1 requires further elucidation.…”

Section: Discussionmentioning

confidence: 99%

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The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

Diefenbach

Davis

Miranda-Saksena

et al. 2016

J Virol

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The alphaherpesviral envelope protein pUS9 has been shown to play a role in the anterograde axonal transport of herpes simplex virus 1 (HSV-1), yet the molecular mechanism is unknown. To address this, we used an in vitro pulldown assay to define a series of five arginine residues within the conserved pUS9 basic domain that were essential for binding the molecular motor kinesin-1. The mutation of these pUS9 arginine residues to asparagine blocked the binding of both recombinant and native kinesin-1. We next generated HSV-1 with the same pUS9 arginine residues mutated to asparagine (HSV-1pUS9KBDM) and then restored them being to arginine (HSV-1pUS9KBDR). The two mutated viruses were analyzed initially in a zosteriform model of recurrent cutaneous infection. The primary skin lesion scores were identical in severity and kinetics, and there were no differences in viral load at dorsal root ganglionic (DRG) neurons at day 4 postinfection (p.i.) for both viruses. In contrast, HSV-1pUS9KBDM showed a partial reduction in secondary skin lesions at day 8 p.i. compared to the level for HSV-1pUS9KBDR. The use of rat DRG neuronal cultures in a microfluidic chamber system showed both a reduction in anterograde axonal transport and spread from axons to nonneuronal cells for HSV-1pUS9KBDM. Therefore, the basic domain of pUS9 contributes to anterograde axonal transport and spread of HSV-1 from neurons to the skin through recruitment of kinesin-1. IMPORTANCEHerpes simplex virus 1 and 2 cause genital herpes, blindness, encephalitis, and occasionally neonatal deaths. There is also increasing evidence that sexually transmitted genital herpes increases HIV acquisition, and the reactivation of HSV increases HIV replication and transmission. New antiviral strategies are required to control resistant viruses and to block HSV spread, thereby reducing HIV acquisition and transmission. These aims will be facilitated through understanding how HSV is transported down nerves and into skin. In this study, we have defined how a key viral protein plays a role in both axonal transport and spread of the virus from nerve cells to the skin. Deletion of the US9 gene, encoding the conserved type II transmembrane viral envelope protein pUS9 (1) (Fig. 1), has been undertaken in a range of Alphaherpesvirinae subfamily members, and neuronal spread has been assessed in several biological models. The relative contribution of pUS9 to neuronal spread within this subfamily was found to differ. Equine herpesvirus type 1 (EHV-1) and bovine herpesvirus type 1 (BHV-1) pUS9 can complement for the loss of pUS9 in swine pathogen pseudorabies virus (PrV) (1). In contrast, varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1) pUS9 are unable to complement for a loss of pUS9 in PrV (1). In PrV (2-5), BHV-1 (6), and BHV-5 (7), pUS9 plays a major role in axonal sorting and/or anterograde axonal transport. For PrV there is also evidence for pUS9-independent anterograde axonal transport of some viral components (8, 9). In HSV-1 the contribution of pUS9 to th...

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Section: Discussionmentioning

confidence: 99%

“…The interaction of PrV pUS9 with kinesin-3 depends on the presence of the additional viral glycoproteins gE and gI (16). Phosphorylation of PrV pUS9, although not essential, does enhance the interaction with kinesin-3 (17).…”

mentioning

confidence: 99%

The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

Diefenbach

Davis

Miranda-Saksena

et al. 2016

J Virol

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“…PRV gE/gI deletion viruses are also impaired in anterograde spread in rat models of retinal infection, despite no impairment of retrograde transport or replication within retinal ganglion neurons (14,15). Similarly, deletion of the PRV gI gene results in impairment of anterograde spread by compartmentalized chamber systems (16,17). However, VZV interactions within neuronal axons have been poorly defined to date due to the high human specificity of the virus, which places limitations on the models available to assess VZV neuronal infection (1,18).…”

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confidence: 99%

Varicella-Zoster Virus Glycoprotein I Is Essential for Spread in Dorsal Root Ganglia and Facilitates Axonal Localization of Structural Virion Components in Neuronal Cultures

Christensen

Steain

Slobedman

et al. 2013

J Virol

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bNeurons of the sensory ganglia are the major site of varicella-zoster virus (VZV) latency and may undergo productive infection during reactivation. Although the VZV glycoprotein E/glycoprotein I (gE/gI) complex is known to be critical for neurovirulence, few studies have assessed the roles of these proteins during infection of dorsal root ganglia (DRG) due to the high human specificity of the virus. Here, we show that the VZV glycoprotein I gene is an important neurotropic gene responsible for mediating the spread of virus in neuronal cultures and explanted DRG. Inoculation of differentiated SH-SY5Y neuronal cell cultures with a VZV gI gene deletion strain (VZV rOka⌬gI) showed a large reduction in the percentage of cells infected and significantly smaller plaque sizes in a comparison with cultures infected with the parental strain (VZV rOka). In contrast, VZV rOka⌬gI was not significantly attenuated in fibroblast cultures, demonstrating a cell type-specific role for VZV gI. Analysis of rOka⌬gI protein localization by immunofluorescent staining revealed aberrant localization of viral glycoprotein and capsid proteins, with little or no staining present in the axons of differentiated SH-SY5Y cells infected with rOka⌬gI, yet axonal vesicle trafficking was not impaired. Further studies utilizing explanted human DRG indicated that VZV gI is required for the spread of virus within DRG. These data demonstrate a role for VZV gI in the cell-to-cell spread of virus during productive replication in neuronal cells and a role in facilitating the access of virion components to axons. V aricella-zoster virus (VZV) is the etiological agent of the human disease varicella (chickenpox) (1). Following primary infection, the virus establishes latency within neurons of the sensory ganglia (2, 3), from where it may reactivate to result in the secondary clinical disease herpes zoster (shingles) (4). Herpes zoster may be followed by a state of debilitating, long-term pain known as postherpetic neuralgia (PHN), which is commonly resistant to many traditional pain therapies (3,5,6).VZV glycoprotein I (gI) is a type I membrane protein encoded by open reading frame 67 (ORF67) and functions primarily as a heterodimer with the most abundant VZV protein, gE (7). Although gI is dispensable in cell culture, deletion of the gene results in an impairment of syncytium formation, delayed replication, and a decrease in infectious virus yields within melanoma cells (8).In the context of neuronal infection, gI has been shown to be dispensable in a rat model of persistent VZV infection, although this host is nonpermissive (9). In a severe combined-immunodeficiency human (SCIDhu) mouse model of VZV infection utilizing human-xenografted dorsal root ganglia (DRG), infection with a VZV mutant lacking the gI gene (rOka⌬gI) resulted in prolonged replication within the DRG and an inability to transition to a persistent state, normally characterized by limited viral transcription (10). In addition, mutation of the cysteine-rich region in VZV gE responsible for ...

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“…The heterodimer of the products of these genes play important role in cell-to-cell spreading of the virus and other connected functions (Snyder et al 2008;Kratchmarov et al 2013;Howard et al 2014;D C Johnson et al 2001). However we were interested in its part in viral gene expression, an area not well documented.…”

Section: Discussionmentioning

confidence: 99%

“…The us7 and us8 genes are preserved across alpha herpes viruses and various functions have been attributed to them, for example: binding to Fc receptors at mucosal surfaces (Knapp et al 1997) or sorting virion particles to cell junctions (David C Johnson et al 2001), as well as promoting anterograde spreading between neurons (Husak et al 2000). It has also been shown that both proteins are essential in axonal transport (Kratchmarov et al 2013) of the virus. Even though DNA replication of the virus is not affected in US7/US8 mutant viruses, their ability of cell-to-cell spreading and virion formation is impaired, thus the mutant viruses are attenuated (Snyder et 6.…”

Section: Viral Life Cyclementioning

confidence: 99%

Transcriptome analysis of Pseudorabies virus reveals selective regulation of different kinetic classes of genes

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Glycoproteins gE and gI Are Required for Efficient KIF1A-Dependent Anterograde Axonal Transport of Alphaherpesvirus Particles in Neurons

Cited by 94 publications

References 53 publications

The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

Varicella-Zoster Virus Glycoprotein I Is Essential for Spread in Dorsal Root Ganglia and Facilitates Axonal Localization of Structural Virion Components in Neuronal Cultures

Transcriptome analysis of Pseudorabies virus reveals selective regulation of different kinetic classes of genes

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