Directional Spread of Alphaherpesviruses in the  Nervous System

Kramer, Tal; Enquist, Lynn W.

doi:10.3390/v5020678

Cited by 92 publications

(85 citation statements)

References 224 publications

(284 reference statements)

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“…To the best of our knowledge, this is the first report of an HSV strategy for CD8 + T cell evasion that regulates HSV-1 pathogenesis and is employed in the CNS. Since HSV-1 UL13 is conserved in herpesviruses in all three Herpesviridae subfamilies, the HSV-1 UL13-mediated immune evasion mechanism may be conserved in other herpesviruses, especially in neurotropic herpesviruses subclassified in the Alphaherpesvirinae subfamily, such as varicella-zoster virus, pseudorabies virus, and equine herpesvirus, which sometimes cause encephalitis (32). At present, whether Us3 and ICP47, which have been reported to downregulate HSV-1-specific MHC-I antigen presentation (5, 6, 8, 9), function in CD8 + T cell evasion in the CNS remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis

Koyanagi¹,

Imai²,

Shindo³

et al. 2017

Journal of Clinical Investigation

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to β-actin (AC15; Sigma-Aldrich), donkey anti-goat IgG-HRP (sc-2020; Santa Cruz Biotechnology Inc.), and sheep anti-mouse IgG, HRPlinked F(ab′) 2 fragment (NA9310; GE) were used for immunoblotting.Statistics. Differences in β-actin mRNA amounts and antigen presentation were statistically analyzed by 1-way ANOVA followed by Tukey's post-test. Differences in survival of infected mice were statistically analyzed by the log-rank test. Differences in other data were statistically analyzed by the Mann-Whitney U test. A P value of 0.05 or less was considered statistically significant.

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Section: Discussionmentioning

confidence: 99%

Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis

Koyanagi¹,

Imai²,

Shindo³

et al. 2017

Journal of Clinical Investigation

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“…Intracellular cargo can simultaneously bind to both dynein and kinesin and move bidirectionally along microtubules. This dynein/kinesin competition for intracellular cargo transport is highly coordinated within cells to maintain subcellular organization (39,41). In a similar fashion, HSV-1, vaccinia virus, and adenovirus utilize the dynein-dynactin motor complex for intracellular transport (37,(42)(43)(44)(45)(46)(47)(48).…”

mentioning

confidence: 99%

Deletion of a Predicted β-Sheet Domain within the Amino Terminus of Herpes Simplex Virus Glycoprotein K Conserved among Alphaherpesviruses Prevents Virus Entry into Neuronal Axons

Jambunathan

Charles

Subramanian

et al. 2016

J Virol

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We have shown previously that herpes simplex virus 1 (HSV-1) lacking expression of the entire glycoprotein K (gK) or expressing gK with a 38-amino-acid deletion (gK⌬31-68 mutation) failed to infect ganglionic neurons after ocular infection of mice. We constructed a new model for the predicted three-dimensional structure of gK, revealing that the gK⌬31-68 mutation spans a well-defined ␤-sheet structure within the amino terminus of gK, which is conserved among alphaherpesviruses. The HSV-1(McKrae) gK⌬31-68 virus was tested for the ability to enter into ganglionic neuronal axons in cell culture of explanted rat ganglia using a novel virus entry proximity ligation assay (VEPLA). In this assay, cell surface-bound virions were detected by the colocalization of gD and its cognate receptor nectin-1 on infected neuronal surfaces. Capsids that have entered into the cytoplasm were detected by the colocalization of the virion tegument protein UL37, with dynein required for loading of virion capsids onto microtubules for retrograde transport to the nucleus. HSV-1(McKrae) gK⌬31-68 attached to cell surfaces of Vero cells and ganglionic axons in cell culture as efficiently as wild-type HSV-1(McKrae). However, unlike the wild-type virus, the mutant virus failed to enter into the axoplasm of ganglionic neurons. This work suggests that the amino terminus of gK is a critical determinant for entry into neuronal axons and may serve similar conserved functions for other alphaherpesviruses. IMPORTANCEAlphaherpesviruses, unlike beta-and gammaherpesviruses, have the unique ability to infect and establish latency in neurons. Glycoprotein K (gK) and the membrane protein UL20 are conserved among all alphaherpesviruses. We show here that a predicted ␤-sheet domain, which is conserved among alphaherpesviruses, functions in HSV-1 entry into neuronal axons, suggesting that it may serve similar functions for other herpesviruses. These results are in agreement with our previous observations that deletion of this gK domain prevents the virus from successfully infecting ganglionic neurons after ocular infection of mice. Herpes simplex virus 1 (HSV-1) encodes at least 26 tegument proteins and 11 virally encoded glycoproteins, as well as several nonglycosylated membrane-associated proteins. Viral glycoproteins gD, gB, gH, and gL serve critical roles in virion entry (1-5). Virion entry is initiated by the binding of glycoproteins gB and gC to glycosaminoglycan (GAG) moieties of cell surface proteoglycans (6). This initial attachment causes the interaction of gD with one or more of its specific receptors, including the herpesvirus entry mediator (HVEM) (HveA), nectin-1 (HVEC), and 3-Osulfated HS. In addition, gB binds to PILR-␣, NMHC-IIA, and myelin-associated glycoprotein (MAG) receptors (7). HSV-1 enters into neurons strictly via a pH-independent fusion of the viral envelope with neuronal plasma membranes (8-10), while it can enter a wide range of nonneuronal cells via either pH-independent or pH-dependent endocytosis (11). Fusion of the vira...

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“…Moreover, opinions differ for the closely related alphaherpesviruses HSV and PRV, as has recently been discussed (28,(36)(37)(38).…”

mentioning

confidence: 99%

Blocking ESCRT-Mediated Envelopment Inhibits Microtubule-Dependent Trafficking of Alphaherpesviruses In Vitro

Kharkwal

Smith

Wilson

2014

J Virol

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Herpes simplex virus (HSV) and, as reported here, pseudorabies virus (PRV) utilize the ESCRT apparatus to drive cytoplasmic envelopment of their capsids. Here, we demonstrate that blocking ESCRT-mediated envelopment using the dominant-negative inhibitor Vps4A-EQ (Vps4A in which glutamate [E] at position 228 in the ATPase active site is replaced by a glutamine [Q]) reduced the ability of HSV and PRV particles to subsequently traffic along microtubules in vitro. HSV and PRV capsid-associated particles with bound green fluorescent protein (GFP)-labeled Vps4A-EQ were readily detected by fluorescence microscopy in cytoplasmic extracts of infected cells. These Vps4A-EQ-associated capsid-containing particles bound to microtubules in vitro but were unable to traffic along them. Using a PRV strain expressing a fluorescent capsid and a fluorescently tagged form of the envelope protein gD, we found that similar numbers of gD-positive and gD-negative capsid-associated particles accumulated in cytoplasmic extracts under our conditions. Both classes of PRV particle bound to microtubules in vitro with comparable efficiency, and similar results were obtained for HSV using anti-gD immunostaining. The gD-positive and gD-negative PRV capsids were both capable of trafficking along microtubules in vitro; however, motile gD-positive particles were less numerous and their trafficking was more sensitive to the inhibitory effects of Vps4A-EQ. We discuss our data in the context of microtubule-mediated trafficking of naked and enveloped alphaherpesvirus capsids. IMPORTANCEThe alphaherpesviruses include several important human pathogens. These viruses utilize microtubule-mediated transport to travel through the cell cytoplasm; however, the molecular mechanisms of trafficking are not well understood. In this study, we have used a cell-free system to examine the requirements for microtubule trafficking and have attempted to distinguish between the movement of so-called "naked" and membrane-associated cytoplasmic alphaherpesvirus capsids. Members of the Alphaherpesvirinae subfamily include herpes simplex virus type 1 (HSV-1) and HSV-2, varicella-zoster virus, and pseudorabies virus (PRV). Like all herpesviruses, members of this subfamily replicate their genomes and assemble DNApackaged capsids in the cell nucleus. It is generally accepted that capsids then bud into the inner nuclear membrane to generate perinuclear virions that subsequently fuse with the outer nuclear membrane to release mature nucleocapsids (also termed "naked" capsids) into the cytoplasm. Naked cytoplasmic herpes capsids subsequently undergo secondary envelopment at a postnuclear organelle to assemble the mature, infectious virion (1-4).By performing subcellular fractionation during a single synchronized wave of HSV egress, we showed that HSV capsids bypass the cis, medial, and trans compartments of the Golgi apparatus (5) and accumulate in a buoyant membrane fraction with the biochemical and antigenic properties of the trans-Golgi network (TGN) and endosomes (5, 6)...

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Directional Spread of Alphaherpesviruses in the Nervous System

Cited by 92 publications

References 224 publications

Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis

Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis

Deletion of a Predicted β-Sheet Domain within the Amino Terminus of Herpes Simplex Virus Glycoprotein K Conserved among Alphaherpesviruses Prevents Virus Entry into Neuronal Axons

Blocking ESCRT-Mediated Envelopment Inhibits Microtubule-Dependent Trafficking of Alphaherpesviruses In Vitro

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