Single amino acid substitutions in the glycoprotein B carboxy terminus influence the fusion from without property of herpes simplex virus type 1

Lingen, Michael; Seck, Tetsu M.; Weise, K.; Falke, D.

doi:10.1099/0022-1317-76-7-1843

Cited by 14 publications

(11 citation statements)

References 19 publications

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“…In our case, the failure of Cyclosporin A and melittin to affect the syncytial properties of 1C3-syn variants appears to be indicative of a probable alteration on gB as responsible for the syn phenotype induced by 1C3. Strains with a mutation in the syn 3 locus affecting gB induce fusion in the presence of Cyclosporin A at a concentration of 150 mM, whereas all other syncytial strains induce cell rounding after infection of cells in the presence of Cyclosporin A [Walev et al, 1994;Lingen et al, 1995]. Consequently, gB would be a main target for the antiviral activity of 1C3.…”

Section: Discussionmentioning

confidence: 97%

Herpes simplex virus type 1 variants arising after selection with an antiviral carrageenan: Lack of correlation between drug susceptibility and syn phenotype

Carlucci

Scolaro

Damonte

2002

Journal of Medical Virology

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Natural carrageenans of diverse structural types isolated from the red seaweed Gigartina skottsbergii were recently identified as potent and selective inhibitors of herpes simplex virus types 1 and 2 (HSV-1 and -2). The mu/nu-carrageenan 1C3 was tested in vitro for its ability to select resistant variants. After serial passages of HSV-1 strain F in Vero cells in the presence of increasing concentrations of 1C3, viruses emerged that were approximately 2- to 10-fold more resistant to 1C3 inhibition than parental virus; these viruses formed large plaques with an altered syncytial phenotype (1C3-syn). Plaque-purified syncytial variants isolated from passages 13 and 14 have shown variable levels of resistance to 1C3, as well as to the other antiviral carrageenans isolated from G. skottsbergii and to other sulfated polysaccharides with known antiviral activity, such as heparin and dextran sulfate 8000, but all the clones were susceptible to acyclovir. The syn phenotype was not related to polysaccharide resistance. All the 1C3-syn variants formed large syncytia in Vero and CV-1 cells but did not induce fusion in other cell types. The growth efficiency in Vero cells, as well as the virulence for mice by intracerebral or intraperitoneal inoculation of 1C3-syn variants, showed no significant alterations in comparison with the parental virus. The syncytial properties were not affected by cyclosporine or melittin, suggesting that an alteration on glycoprotein gB could be responsible for the syn phenotype induced by 1C3.

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Section: Discussionmentioning

confidence: 97%

Herpes simplex virus type 1 variants arising after selection with an antiviral carrageenan: Lack of correlation between drug susceptibility and syn phenotype

Carlucci

Scolaro

Damonte

2002

Journal of Medical Virology

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“…Recombinant 17-syn3 resulted from cotransfection experiments of 17 syn + genomic DNA and the cloned carboxy-terminal portion of ANG path (Lingen et al 1995). This recombinant showed the syncytial phenotype of strain ANG path in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…HSV-1 strains ANG path (Kaerner et al 1983), 17 syn + (Subak-Sharpe et al 1974) and recombinants 27/III and 17-syn3 (Lingen et al 1995) were used. The isolates G3-ZA, RM1-fr and RM6-fr are described here (see Table 1).…”

Section: Cell Culture and Virusesmentioning

confidence: 99%

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Mixed vaginal infections of Balb/c mice with low virulent herpes simplex type 1 strains result in restoration of virulence properties: vaginitis/vulvitis and neuroinvasiveness

Lingen

Hengerer

Falke

1997

Medical Microbiology and Immunology

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Vaginal infections of BALB/c Ann mice with herpes simplex virus type 1 (HSV-1) were studied. Mice were inoculated with virulent strains ANG path and 17 syn+ or low-virulent recombinant strains 27/III and 17-syn3 that differ from parental strains in their glycoprotein B (gB) gene sequences. When low-virulent strains were inoculated separately, no vaginitis/vulvitis was produced despite replication in the vagina. In contrast, after coinfection of mice with the two low-virulent strains, vaginitis/vulvitis was produced and virus could be recovered from the central nervous system (CNS). Two of the CNS isolates produced vaginitis/vulvitis, neuroinvasiveness and death of mice after vaginal infection. Restriction fragment analysis and sequencing were used to assess recombination events in the gB gene sequence of the CNS isolates. After mixed vaginal infection recombination between non-virulent HSV strains occurs, resulting in vaginitis/vulvitis and neuroinvasiveness. No correlation was detected between the syncytial phenotype and local vaginal virulence. Virulence of HSV is not solely dependent on gB function; it seems to be more probable that several genes act in concert to induce virulence and neuroinvasiveness.

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“…Thus, this region is a putative fusion loop in gB-1 (35). Several mutations resulting in a hyperfusion phenotype have been mapped to the cytoplasmic tail of gB-1, indicating that this region plays an important role in regulating the fusogenic activity of the protein (4,21,24,25,46,63,77). Mutations leading to reversion of the syncytium-forming phenotype of gB-1 mutants have been mapped to the UL45 envelope protein (33), suggesting that UL45 may interact with gB-1 and regulate fusogenic activity.…”

mentioning

confidence: 99%

Multiple Peptides Homologous to Herpes Simplex Virus Type 1 Glycoprotein B Inhibit Viral Infection

Akkarawongsa

Pocaro

Case

et al. 2009

Antimicrob Agents Chemother

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The 773-residue ectodomain of the herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) has been resistant to the use of mutagenic strategies because the majority of the induced mutations result in defective proteins. As an alternative strategy for the identification of functionally important regions and novel inhibitors of infection, we prepared a library of overlapping peptides homologous to the ectodomain of gB and screened for the ability of the peptides to block infection. Seven of 138 15-mer peptides inhibited infection by more than 50% at a concentration of 100 M. Three peptides (gB94, gB122, and gB131) with 50% effective concentrations (EC 50 s) below 20 M were selected for further studies. The gB131 peptide (residues 681 to 695 in HSV-1 gB [gB-1]) was a specific entry inhibitor (EC 50 , ϳ12 M). The gB122 peptide (residues 636 to 650 in gB-1) blocked viral entry (EC 50 , ϳ18 M), protected cells from infection (EC 50 , ϳ72 M), and inactivated virions in solution (EC 50 , ϳ138 M). We were unable to discern the step or steps inhibited by the gB94 peptide, which is homologous to residues 496 to 510 in gB-1. Substitution of a tyrosine in the gB122 peptide (Y640 in full-length gB-1) reduced the antiviral activity eightfold, suggesting that this residue is critical for inhibition. This peptide-based strategy could lead to the identification of functionally important regions of gB or other membrane proteins and identify novel inhibitors of HSV-1 entry.Herpes simplex virus type 1 (HSV-1) is a significant human pathogen that primarily causes mucocutaneous ulcers. Less common but more serious infections can result in encephalitis, blinding keratitis, or neonatal herpes (78). Several antivirals are approved for the treatment of HSV infections but are ineffective in certain situations and do not eliminate latent infections (20,56,65). Thus, new strategies are needed to deal with these infections.HSV-1 infection is initiated by the binding of glycoprotein C (gC) to cell surface heparan sulfate (69,71,72). The HSV-1 gB protein (gB-1) can also bind to heparan sulfate proteoglycan, but the binding is less efficient (37). Following attachment, gD binds to any of four cellular coreceptors, including HVEM (herpesvirus entry mediator), nectin 1, nectin 2, or 3-O-sulfated heparan sulfate, resulting in a conformational change in gD (18,28,41,50,51). The conformational change in gD is then thought to trigger the formation of the fusion complex, which includes gB and the gH-gL heterodimer. The coexpression of gD, gB, and gH-gL in the same cell results in cell-cell fusion, indicating that these four proteins constitute the minimal fusion apparatus (10, 24, 52, 61, 75). It has been suggested that gH-gL and gB are recruited to gD independently of one another and possibly interact with each other (3). Recent studies show that HSV-1 fusion is mediated through a hemifusion intermediate involving gH-gL but that the complete fusion event requires the action of gB (73). gB-1 interacts with the cell surface (7,59,60), and a cell surface...

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Single amino acid substitutions in the glycoprotein B carboxy terminus influence the fusion from without property of herpes simplex virus type 1

Cited by 14 publications

References 19 publications

Herpes simplex virus type 1 variants arising after selection with an antiviral carrageenan: Lack of correlation between drug susceptibility and syn phenotype

Herpes simplex virus type 1 variants arising after selection with an antiviral carrageenan: Lack of correlation between drug susceptibility and syn phenotype

Mixed vaginal infections of Balb/c mice with low virulent herpes simplex type 1 strains result in restoration of virulence properties: vaginitis/vulvitis and neuroinvasiveness

Multiple Peptides Homologous to Herpes Simplex Virus Type 1 Glycoprotein B Inhibit Viral Infection

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