Tyrosine 116 of the Herpes Simplex Virus Type 1 IEα22 Protein Is an Ocular Virulence Determinant and Potential Phosphorylation Site

Brandt, Curtis R.; Kolb, Aaron W.

doi:10.1167/iovs.03-0582

Cited by 16 publications

(14 citation statements)

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“…Deletion of certain genes from the virus can have significant effects on virulence, but in nature it is more likely that virulence differences are due to effects of multiple genes and the combination of alleles carried by a given strain of virus. This is supported by a study showing that transferring different combinations of genes from a moderately virulent strain (CJ394) into a highly attenuated strain of virus (OD4) 25,26 resulted in different virulence patterns in mice. At least seven genes were shown to be involved in the virulence differences.…”

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confidence: 85%

Sequence Variation in the Herpes Simplex Virus U_S1 Ocular Virulence Determinant

Kolb

Schmidt

Dyer

et al. 2011

Invest. Ophthalmol. Vis. Sci.

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These results suggest that significant sequence variation exists in the U(S)1 gene, that the α22 protein contains a conserved central core region with structurally variable regions at the amino- and carboxyl termini, that 10 amino acids are conserved in α-herpes U(S)1 homologs, and that additional host proteins may interact with the HSV-1 U(S)1 and U(S)1.5 proteins. This information will be valuable in designing further studies on structure-function relationships and on the role these play in host-range determination and keratitis.

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confidence: 85%

Sequence Variation in the Herpes Simplex Virus U_S1 Ocular Virulence Determinant

Kolb

Schmidt

Dyer

et al. 2011

Invest. Ophthalmol. Vis. Sci.

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“…Epistatic interactions between host genes affecting susceptibility to HSV-1 latency have been identified (17). We previously showed that coinheritance of amino acids at two locations in the ICP22 protein affected ocular virulence, but it was an example of intragenic epistasis (within one gene) (18). While epistatic interactions between human cytomegalovirus (hCMV) genes have been described (19), this is the first identification of an intergenic interaction for virulence in HSV-1.…”

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confidence: 87%

Mapping Murine Corneal Neovascularization and Weight Loss Virulence Determinants in the Herpes Simplex Virus 1 Genome and the Detection of an Epistatic Interaction between the UL and IRS/US Regions

Lee

Kolb

Larsen

et al. 2016

J Virol

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Herpes simplex virus 1 (HSV-1) most commonly causes recrudescent labial ulcers; however, it is also the leading cause of infectious blindness in developed countries. Previous research in animal models has demonstrated that the severity of HSV-1 ocular disease is influenced by three main factors: host innate immunity, host immune response, and viral strain. We have previously shown that mixed infection with two avirulent HSV-1 strains (OD4 and CJ994) results in recombinants with a wide range of ocular disease phenotype severity. Recently, we developed a quantitative trait locus (QTL)-based computational approach (vQTLmap) to identify viral single nucleotide polymorphisms (SNPs) predicted to influence the severity of the ocular disease phenotypes. We have now applied vQTLmap to identify HSV-1 SNPs associated with corneal neovascularization and mean peak percentage weight loss (MPWL) using 65 HSV-1 OD4-CJ994 recombinants. The vQTLmap analysis using Random Forest for neovascularization identified phenotypically meaningful nonsynonymous SNPs in the ICP4, UL41 (VHS), UL42, UL46 (VP11/ 12), UL47 (VP13/14), UL48 (VP22), US3, US4 (gG), US6 (gD), and US7 (gI) coding regions. The ICP4 gene was previously identified as a corneal neovascularization determinant, validating the vQTLmap method. Further analysis detected an epistatic interaction for neovascularization between a segment of the unique long (UL) region and a segment of the inverted repeat short (IRS)/unique short (US) region. Ridge regression was used to identify MPWL-associated nonsynonymous SNPs in the UL1 (gL), UL2, UL4, UL49 (VP22), UL50, and ICP4 coding regions. The data provide additional insights into virulence gene and epistatic interaction discovery in HSV-1. IMPORTANCEHerpes simplex virus 1 (HSV-1) typically causes recurrent cold sores; however, it is also the leading source of infectious blindness in developed countries. Corneal neovascularization is critical for the progression of blinding ocular disease, and weight loss is a measure of infection severity. Previous HSV-1 animal virulence studies have shown that the severity of ocular disease is partially due to the viral strain. In the current study, we used a recently described computational quantitative trait locus (QTL) approach in conjunction with 65 HSV-1 recombinants to identify viral single nucleotide polymorphisms (SNPs) involved in neovascularization and weight loss. Neovascularization SNPs were identified in the ICP4, VHS, UL42, VP11/12, VP13/14, VP22, gG, US3, gD, and gI genes. Further analysis revealed an epistatic interaction between the UL and US regions. MPWL-associated SNPs were detected in the UL1 (gL), UL2, UL4, VP22, UL50, and ICP4 genes. This approach will facilitate future HSV virulence studies. Herpes simplex virus 1 (HSV-1) is most commonly responsible for recurrent vesicular lesions of the oral mucosa; however, HSV-1 is increasingly found in genital infections, and it is the leading cause of infectious blindness and sporadic encephalitis in developed countries (1-4). The ...

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“…Tyrosine phosphorylation is involved in the replication of several herpesviruses (Geiss et al, 2001;Ren et al, 2001) and in shifting protein translocation from the cytoplasm to the nucleus during productive virus infection (Pomeranz and Blaho, 1999). Phosphorylation of VZV ORF63 is associated with its subcellular localization and transcriptional regulatory properties (Habran et al, 2005;Mueller et al, 2010), and phosphorylation of ICP22 is involved in HSV-1 virulence (Brandt and Kolb, 2003). Therefore, PICP22 phosphorylation may also play an important role during PRV infection, perhaps in modulating its subcellular localization or other uncharacterized functions, such as transcriptional regulation.…”

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confidence: 99%

Molecular cloning and characterization of the pseudorabies virus US1 gene

Chen

Zhao

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Using polymerase chain reaction, a 1050-bp sequence of the US1 gene was amplified from the pseudorabies virus (PRV) Becker strain genome; identification of the US1 gene was confirmed by further cloning and sequencing. Bioinformatics analysis indicated that the PRV US1 gene encodes a putative polypeptide with 349 amino acids. The encoded protein, designated PICP22, had a conserved Herpes_IE68 domain, which was found to be closely related with the herpes virus immediate early regulatory protein family and is highly conserved among the counterparts encoded by Herpes_IE68 genes. Multiple nucleic acid sequence and amino acid sequence alignments suggested that the product of PRV US1 has a relatively higher homology with ICP22-like proteins of genus Varicellovirus than with those of other genera of Alphaherpesvirinae. In addition, phylogenetic analysis showed that PRV US1 has a close evolutionary relationship with members of the genus Varicellovirus, especially Equid herpes virus 1 (EHV-1), EHV-4 and EHV-9. Antigen prediction indicated that several potential B-cell epitopes are located in PICP22. Also, subcellular localization analysis demonstrated that PICP22 is predominantly located in the cytoplasm, suggesting that it might function as a cytoplasmic-targeted protein.

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Tyrosine 116 of the Herpes Simplex Virus Type 1 IEα22 Protein Is an Ocular Virulence Determinant and Potential Phosphorylation Site

Cited by 16 publications

References 53 publications

Sequence Variation in the Herpes Simplex Virus U_S1 Ocular Virulence Determinant

Sequence Variation in the Herpes Simplex Virus U_S1 Ocular Virulence Determinant

Mapping Murine Corneal Neovascularization and Weight Loss Virulence Determinants in the Herpes Simplex Virus 1 Genome and the Detection of an Epistatic Interaction between the UL and IRS/US Regions

Molecular cloning and characterization of the pseudorabies virus US1 gene

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Tyrosine 116 of the Herpes Simplex Virus Type 1 IEα22 Protein Is an Ocular Virulence Determinant and Potential Phosphorylation Site

Cited by 16 publications

References 53 publications

Sequence Variation in the Herpes Simplex Virus US1 Ocular Virulence Determinant

Sequence Variation in the Herpes Simplex Virus US1 Ocular Virulence Determinant

Mapping Murine Corneal Neovascularization and Weight Loss Virulence Determinants in the Herpes Simplex Virus 1 Genome and the Detection of an Epistatic Interaction between the UL and IRS/US Regions

Molecular cloning and characterization of the pseudorabies virus US1 gene

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Sequence Variation in the Herpes Simplex Virus U_S1 Ocular Virulence Determinant

Sequence Variation in the Herpes Simplex Virus U_S1 Ocular Virulence Determinant