Herpes Simplex Virus Type 1 gK Is Required for gB-Mediated Virus-Induced Cell Fusion, While neither gB and gK nor gB and UL20p Function Redundantly in Virion De-Envelopment

Melancon, Jeffrey M.; Luna, Rafael E.; Foster, Timothy P.; Kousoulas, Konstantin G.

doi:10.1128/jvi.79.1.299-313.2005

Cited by 55 publications

(67 citation statements)

References 61 publications

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“…3A, left panel), the gB-null virus does not downregulate CD1d (right panel). Although the gB-null virus is able to complete the replication cycle and release virions like wild-type viruses, its replication in noncomplementing cells is much weaker than wild-type viruses, reflected in the much smaller plaque size at 48 h postinfection (47). This is probably due to the previously described interaction of gB with the ER stress sensor, protein kinase-like ER kinase (PERK) (50).…”

Section: Resultsmentioning

confidence: 71%

Herpes Simplex Virus 1 Glycoprotein B and US3 Collaborate To Inhibit CD1d Antigen Presentation and NKT Cell Function

Rao

Pham

Kulkarni

et al. 2011

J Virol

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Herpes simplex viruses (HSVs) are prevalent human pathogens that establish latency in human neuronal cells and efficiently evade the immune system. It has been a major medical challenge to eradicate them and, despite intensive efforts, an effective vaccine is not available. We previously showed that upon infection of antigen-presenting cells, HSV type 1 (HSV-1) rapidly and efficiently downregulates the major histocompatibility complex class I-like antigen-presenting molecule, CD1d, and potently inhibits its recognition by CD1d-restricted natural killer T (NKT) cells. It suppresses CD1d expression primarily by inhibiting its recycling to the cell surface after endocytosis. We identify here the viral glycoprotein B (gB) as the predominant CD1d-interacting protein. gB initiates the interaction with CD1d in the endoplasmic reticulum and stably associates with it throughout CD1d trafficking. However, an additional HSV-1 component, the serine-threonine kinase US3, is required for optimal CD1d downregulation. US3 expression in infected cells leads to gB enrichment in the trans-Golgi network (TGN) and enhances the relocalization of both gB and CD1d to this compartment, suggesting that following internalization CD1d is translocated from the endocytic pathway to the TGN by its association with gB. Importantly, both US3 and gB are required for efficient inhibition of CD1d antigen presentation and NKT cell activation. In summary, our results suggest that HSV-1 uses gB and US3 to rapidly inhibit NKT cell function in the initial antiviral response.

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Section: Resultsmentioning

confidence: 71%

Herpes Simplex Virus 1 Glycoprotein B and US3 Collaborate To Inhibit CD1d Antigen Presentation and NKT Cell Function

Rao

Pham

Kulkarni

et al. 2011

J Virol

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“…Four proteins unique to alphaherpesviruses are also highly conserved (UL20, UL45, VP13-14 [UL47], and gK [UL53]). The functions of two of these, UL20 and UL45, are not well known, and their conservation indicates that further investigation of their function is warranted (138)(139)(140)(141)(142). A third protein, VP13-14 (UL47) modulates transactivator VP16 (UL48) to induce high levels of immediate early gene expression (143,144).…”

Section: Resultsmentioning

confidence: 99%

“…A third protein, VP13-14 (UL47) modulates transactivator VP16 (UL48) to induce high levels of immediate early gene expression (143,144). The proteins UL20, UL45, and gK have been proposed to interact with each other and with the herpesvirus fusion machinery (138)(139)(140)(141)(142).…”

Section: Resultsmentioning

confidence: 99%

Evolution and Diversity in Human Herpes Simplex Virus Genomes

Szpara

Gatherer

Ochoa

et al. 2014

J Virol

193

280

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gHerpes simplex virus 1 (HSV-1) causes a chronic, lifelong infection in >60% of adults. Multiple recent vaccine trials have failed, with viral diversity likely contributing to these failures. To understand HSV-1 diversity better, we comprehensively compared 20 newly sequenced viral genomes from China, Japan, Kenya, and South Korea with six previously sequenced genomes from the United States, Europe, and Japan. In this diverse collection of passaged strains, we found that one-fifth of the newly sequenced members share a gene deletion and one-third exhibit homopolymeric frameshift mutations (HFMs). Individual strains exhibit genotypic and potential phenotypic variation via HFMs, deletions, short sequence repeats, and single-nucleotide polymorphisms, although the protein sequence identity between strains exceeds 90% on average. In the first genome-scale analysis of positive selection in HSV-1, we found signs of selection in specific proteins and residues, including the fusion protein glycoprotein H. We also confirmed previous results suggesting that recombination has occurred with high frequency throughout the HSV-1 genome. Despite this, the HSV-1 strains analyzed clustered by geographic origin during whole-genome distance analysis. These data shed light on likely routes of HSV-1 adaptation to changing environments and will aid in the selection of vaccine antigens that are invariant worldwide. Herpes simplex virus 1 (HSV-1; species Human herpesvirus 1, genus Simplexvirus, subfamily Alphaherpesvirinae, family Herpesviridae, order Herpesvirales) is among the most successful human pathogens in terms of its global distribution, longevity in the host, and mild symptoms among the great majority of those exposed (1-4). HSV-1 is a large, enveloped DNA virus that infects lytically at epithelial surfaces and establishes a lifelong, latent infection in sensory neurons. HSV-1 infection produces a wide range of symptoms, ranging from few or none in many seropositive individuals to periodic lesions on epithelial surfaces in a significant proportion of people and to lethal encephalitis as an extreme manifestation in a few. There is no vaccine at present (5, 6). Studies in animal models have characterized the ways in which genetic variation between viral strains can influence the symptoms of pathology, including lesion severity and rates of reactivation from latency. The most recent phase III vaccine trial for HSV failed to provide protection from infection (7, 8), and one contributing factor to this failure may well be variation among HSV isolates found in the field.Based on early restriction fragment length polymorphism (RFLP) analyses, HSV-1 has been described as more diverse than HSV-2 (9-11). In contrast to both HSV-1 and HSV-2, the related human alphaherpesvirus, varicella-zoster virus (VZV), has relatively low interstrain diversity (12-15). Decades of research comparing RFLP bands, polypeptide size, and PCR-based sequence analysis have revealed that HSV-1 strains vary between individuals, over sequential isolates from the s...

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“…Another possibility is that apoE influences isoform-dependent cellular susceptibility to HSV-1. Initial binding of HSV-1 to cells can be mediated by HSV-1 glycoprotein gB and gC (Melancon et al, 2005;Subramanian and Geraghty, 2007), and purified gB from HSV-1 can directly interact with apoE (Subramanian and Geraghty, 2007). Both apoE and HSV-1 can enter cells via a heparan sulphate proteoglycan (HSPG) binding site (Shieh et al, 1992), which results in the accumulation of both within the cell.…”

Section: Discussionmentioning

confidence: 99%

Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1

Bhattacharjee

Neumann

Foster

et al. 2008

Experimental Eye Research

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The isoform-specific role of human apolipoprotein E (apoE) has been assessed in a mouse model of ocular herpes. Female, age-matched transgenic mice knocked-in for the human allele apoE3 or apoE4 and their parent C57Bl/6 mice were inoculated corneally with HSV-1 strain KOS. Ocular HSV-1 pathogenesis was monitored through viral replication and clinical progression of stromal opacity and neovascularization by slit-lamp examination. Establishment of latency was determined by analysis of HSV-1 DNA (copy number) by specific real-time PCR in the cornea, trigeminal ganglia (TG), and brain. Representative groups of transgenic mice were sacrificed for the analysis of gene expression of vascular endothelial growth factor (VEGF) by reverse-transcription PCR, and apoE expression by Western blot analysis. At 6 days post-infection (P.I.), the ocular infectious HSV-1 titer was significantly higher (p < 0.05) in apoE4 mice compared with apoE3 and C57Bl/6 mice. Corneal neovascularization in apoE4 mice was significantly higher (p < 0.05) than apoE3 and C57Bl/6 mice. The onset of corneal opacity in apoE4 mice was accelerated during days 9--11 P.I.; however, no significant difference in severity was seen on P.I. days 15 and beyond. At 28 days P.I., infected mice of all genotypes had no significant differences in copy numbers (range 0--15) of HSV-1 DNA in their corneas, indicating that HSV-1 DNA copy numbers in cornea are independent of apoE isoform regulation. At 28 days P.I., both apoE4 and C57Bl/6 mice had a significantly higher (p = 0.001) number of copies of HSV-1 DNA in TG compared with apoE3. ApoE4 mice also had significantly higher (p = 0.001) copies of HSV-1 DNA in their TGs compared with C57Bl/6 mice. In brain, both apoE4 and C57Bl/6 mice had significantly higher numbers (p ≤ 0.03) of copies of HSV-1 DNA compared with apoE3 mice. However, the number of HSV-1 DNA copies in the brain of C57Bl/6 mice was not significantly different than that of apoE4 (p = 0.1). Comparative molecular analysis between apoE3 and apoE4 mice on selected days between 7 and 28 P.I., inclusive, revealed that the corneas of apoE4 mice expressed VEGF. None of the corneas in the apoE3 mice expressed VEGF Corresponding author: James M. Hill, Ph.D., LSU Eye Center, 2020 Gravier Street, Suite B, New Orleans, LA 70112, USA, Telephone: (504) 568 2274, Fax: (504) 568 2385, E-mail: jhill@lsuhsc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Western blot analysis showed proteolytic cleavage of the apoE protein in the corneas of the apoE4 mice. Through days 14 to 28 P.I., a ~29 kDa C-terminal truncated apoE f...

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Herpes Simplex Virus Type 1 gK Is Required for gB-Mediated Virus-Induced Cell Fusion, While neither gB and gK nor gB and UL20p Function Redundantly in Virion De-Envelopment

Cited by 55 publications

References 61 publications

Herpes Simplex Virus 1 Glycoprotein B and US3 Collaborate To Inhibit CD1d Antigen Presentation and NKT Cell Function

Herpes Simplex Virus 1 Glycoprotein B and US3 Collaborate To Inhibit CD1d Antigen Presentation and NKT Cell Function

Evolution and Diversity in Human Herpes Simplex Virus Genomes

Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1

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