Multiple Determinants Contribute to the Virulence of HSV Ocular and CNS Infection and Identification of Serine 34 of the US1 Gene as an Ocular Disease Determinant

Brandt, Curtis R.; Kolb, Aaron W.; Shah, Dipti; Pumfery, Anne; Kintner, Randall L.; Jaehnig, Eric J.; Gompel, Jamie J. Van

doi:10.1167/iovs.02-1105

Cited by 27 publications

(24 citation statements)

References 90 publications

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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.…”

mentioning

confidence: 85%

“…One gene that, when transferred from CJ394 into OD4, increased ocular virulence but not neurovirulence was U S 1, and two sequence changes, S34A and Y116C, that must occur together, were suggested to play a role in the difference in virulence. 25,26 The HSV-1 U S 1 protein (␣22) is an immediate early (␣) gene that regulates several processes in infected cells. In concert with the U S 3 and U L 13 kinases, it alters the phosphorylation of RNA polymerase II, and this is thought to target Pol II to the viral genome.…”

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confidence: 99%

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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%

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confidence: 99%

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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“…In nature, the virulence of any given viral strain is most likely the result of the effects of the expression of a variety of viral genes. How these genes and their products interact with each other and with host proteins determines the outcome of the disease [81,82]. A natural BoHV-1 recombinant deleted in the gene encoding glycoprotein E was isolated in vitro [21].…”

Section: Virulence Of Recombinant Virusesmentioning

confidence: 99%

“…Virulent recombinants can be generated following coinoculation of mice with two avirulent strains of HSV-1 [19]. Mixed infection with two avirulent strains of HSV-1 can result in synergistic increases in the severity of ocular or central nervous system virulence, primarily through the generation of recombinant viruses [59,81,[85][86][87]. This is not always the case: interspecific recombinants between virulent HSV-1 and HSV-2 lost the parental phenotype [88].…”

Section: Virulence Of Recombinant Virusesmentioning

confidence: 99%

Recombination in alphaherpesviruses

et al. 2005

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Within the Herpesviridae family, Alphaherpesvirinae is an extensive subfamily which contains numerous mammalian and avian viruses. Given the low rate of herpesvirus nucleotide substitution, recombination can be seen as an essential evolutionary driving force although it is likely underestimated. Recombination in alphaherpesviruses is intimately linked to DNA replication. Both viral and cellular proteins participate in this recombination-dependent replication. The presence of inverted repeats in the alphaherpesvirus genomes allows segment inversion as a consequence of specific recombination between repeated sequences during DNA replication. High molecular weight intermediates of replication, called concatemers, are the site of early recombination events. The analysis of concatemers from cells coinfected by two distinguishable alphaherpesviruses provides an efficient tool to study recombination without the bias introduced by invisible or non-viable recombinants, and by dominance of a virus over recombinants. Intraspecific recombination frequently occurs between strains of the same alphaherpesvirus species. Interspecific recombination depends on enough sequence similarity to enable recombination between distinct alphaherpesvirus species. The most important prerequisite for successful recombination is coinfection of the individual host by different virus strains or species. Consequently the following factors affecting the distribution of different viruses to shared target cells need to be considered: dose of inoculated virus, time interval between inoculation of the first and the second virus, distance between the marker mutations, genetic homology, virulence and latency. Recombination, by exchanging genomic segments, may modify the virulence of alphaherpesviruses. It must be carefully assessed for the biosafety of antiviral therapy, alphaherpesvirus-based vectors and live attenuated vaccines.

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“…It was not necessarily surprising that the WR strain was virulent, as this strain was derived by brain passage in mice (37). We previously showed that the ocular virulence phenotype of a given HSV strain depends on the contributions of multiple viral genes (38)(39)(40), and it is likely that VACV is similar. The availability of two strains of virus with different virulence properties will allow us to use our recently reported virulence quantitative trait locus mapping procedure (40) to identify and characterize virulence genes in ocular infections.…”

Section: Fig 9 Flow Cytometry Analysis Of T-cell Subsets In Infected mentioning

confidence: 99%

Both CD8⁺and CD4⁺T Cells Contribute to Corneal Clouding and Viral Clearance following Vaccinia Virus Infection in C57BL/6 Mice

Larsen

Clausius

Kolb

et al. 2016

J Virol

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Vaccinia virus (VACV) keratitis is a serious complication following smallpox vaccination and can lead to blindness. The pathological mechanisms involved in ocular VACV infection are poorly understood. Previous studies have used rabbits, but the lack of immune reagents and transgenic or knockout animals makes them less suitable for mechanistic studies. We report that infection of C57BL/6 mice with 1 ؋ 10 7 PFU of vaccinia virus strain WR results in blepharitis, corneal neovascularization, and stromal keratitis. The DryVax strain of VACV was completely attenuated. Infection required corneal scarification and replication-competent virus, and the severity of ocular disease was similar in 4-to 6-week-old and 1-year-old mice. Viral titers peaked at approximately 1 ؋ 10 6 PFU on day 5 postinfection, and virus had not cleared by day 13 postinfection. Neutrophils were found in the peripheral cornea on day 1 after infection and then declined, followed by infiltration of both CD4؉ and CD8 ؉ T cells, which remained peripheral throughout the infection. Blood vessel growth extended 2 to 5 mm into the cornea from the limbus. Infection of CD4 ؊/؊ , CD8 ؊/؊ , or antibody-depleted mice resulted in similar disease severity and corneal clouding, indicating that both T-cell subsets were involved in the immunopathological response. Depletion of both CD4؉ and CD8 ؉ T cells resulted in significantly more severe disease and failure to clear the virus. On the basis of our results, the pathology of VACV keratitis is significantly different from that of herpes simplex virus keratitis. Further studies are likely to reveal novel information regarding virulence and immune responses to viral ocular infection. IMPORTANCEPotentially blinding eye infections can occur after vaccination for smallpox. Very little is known about the pathological mechanisms that are involved, and the information that is available was generated using rabbit models. The lack of immunological reagents for rabbits makes such studies difficult. We characterized a mouse model of vaccinia virus ocular disease using C57BL/6 mice and strain WR and show that both CD4؉ and CD8 ؉ T-cell subsets play a role in the blinding eye disease and in controlling virus replication. On the basis of these results, vaccinia virus keratitis is significantly different from herpes simplex virus keratitis, and further studies using this model should generate novel insights into immunopathological responses to viral ocular infection. In 1977, the World Health Organization reported the last known case of naturally acquired smallpox virus infection (1). The eradication of smallpox was accomplished by rigorous vaccination using vaccinia virus (VACV) and a contact tracing program. Shortly thereafter, the United States stopped vaccination of the general population. In response to increased terrorism incidents, including bioterror events, the U.S. government expanded the list of those who should be vaccinated to include first responders and stockpiled smallpox vaccine and vaccinia virus immune gl...

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Multiple Determinants Contribute to the Virulence of HSV Ocular and CNS Infection and Identification of Serine 34 of the US1 Gene as an Ocular Disease Determinant

Cited by 27 publications

References 90 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

Recombination in alphaherpesviruses

Both CD8⁺and CD4⁺T Cells Contribute to Corneal Clouding and Viral Clearance following Vaccinia Virus Infection in C57BL/6 Mice

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Multiple Determinants Contribute to the Virulence of HSV Ocular and CNS Infection and Identification of Serine 34 of the US1 Gene as an Ocular Disease Determinant

Cited by 27 publications

References 90 publications

Sequence Variation in the Herpes Simplex Virus US1 Ocular Virulence Determinant

Sequence Variation in the Herpes Simplex Virus US1 Ocular Virulence Determinant

Recombination in alphaherpesviruses

Both CD8+and CD4+T Cells Contribute to Corneal Clouding and Viral Clearance following Vaccinia Virus Infection in C57BL/6 Mice

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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

Both CD8⁺and CD4⁺T Cells Contribute to Corneal Clouding and Viral Clearance following Vaccinia Virus Infection in C57BL/6 Mice