Abstract

Ocular disease caused by herpes simplex virus affects up to 500,000 people in the United States. It is known that innate host resistance, host immune responses, and viral genes affect the severity of ocular disease. Several viral genes that affect virulence are known, but their role in ocular infection is not known. In addition, multiple viral genes likely interact to promote virulence and little is known about such interactions and how they affect virulence. Previously, it was shown that mixed ocular infection with two HSV-1 strains (OD4 and CJ394) resulted in a synergistic increase in both ocular disease and neurovirulence. The overall goal of the project is to identify the virulence determinants in CJ394 and OD4 and study their role in ocular disease. Marker transfer studies have mapped one determinant that transfers increased ocular disease to a 1.9 Kb region of the HSV-1 genome that contains part of the unique short (US) region of the genome (US1/1.5 genes) and a portion of the repeated regions flanking US. Sequencing a portion of the 1.9 Kb region has identified a frameshift/premature termination mutation in OD4 that would truncate the US1 ((22) protein at amino acid 68. The focus of the proposal is to confirm this represents one virulence determinant. At least two other regions of the CJ394 genome also transfer partial ocular virulence, suggesting multiple genes cooperate in increasing ocular disease.
The Specific Aims are to (1) genotypically confirm that the OD4 US1 gene is mutated compared to CJ394, (2) phenotypically confirm that (22 functions are missing or compromised in OD4 but are normal in CJ394, (3) localize the virulence determinants in the other CJ394 fragments (EcoRI O and D), and (4) test the hypothesis that multiple virulence determinants cooperate to increase ocular virulence. This work will clarify the interactions between virulence genes, discover new virulence genes, and provide information that will improve therapy for ocular HSV infections.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007336-13
Application #
6384582
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1987-09-30
Project End
2002-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
13
Fiscal Year
2001
Total Cost
$185,406
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Kolb, Aaron W; Ané, Cécile; Brandt, Curtis R (2013) Using HSV-1 genome phylogenetics to track past human migrations. PLoS One 8:e76267
Kolb, Aaron W; Schmidt, Timothy R; Dyer, David W et al. (2011) Sequence variation in the herpes simplex virus U(S)1 ocular virulence determinant. Invest Ophthalmol Vis Sci 52:4630-8
Kolb, Aaron W; Adams, Marie; Cabot, Eric L et al. (2011) Multiplex sequencing of seven ocular herpes simplex virus type-1 genomes: phylogeny, sequence variability, and SNP distribution. Invest Ophthalmol Vis Sci 52:9061-73
Altmann, S E; Jones, J C; Schultz-Cherry, S et al. (2009) Inhibition of Vaccinia virus entry by a broad spectrum antiviral peptide. Virology 388:248-59
Akkarawongsa, Radeekorn; Potocky, Terra B; English, Emily P et al. (2008) Inhibition of herpes simplex virus type 1 infection by cationic beta-peptides. Antimicrob Agents Chemother 52:2120-9
Cai, Suping; Brandt, Curtis R (2008) Induction of interleukin-6 in human retinal epithelial cells by an attenuated Herpes simplex virus vector requires viral replication and NFkappaB activation. Exp Eye Res 86:178-88
Teuton, Jeremy R; Brandt, Curtis R (2007) Sialic acid on herpes simplex virus type 1 envelope glycoproteins is required for efficient infection of cells. J Virol 81:3731-9
Brandt, Curtis R; Akkarawongsa, Radeekorn; Altmann, Sharon et al. (2007) Evaluation of a theta-defensin in a Murine model of herpes simplex virus type 1 keratitis. Invest Ophthalmol Vis Sci 48:5118-24
Bultmann, Hermann; Teuton, Jeremy; Brandt, Curtis R (2007) Addition of a C-terminal cysteine improves the anti-herpes simplex virus activity of a peptide containing the human immunodeficiency virus type 1 TAT protein transduction domain. Antimicrob Agents Chemother 51:1596-607
Akkarawongsa, Radeekorn; Cullinan, Amy E; Zinkel, Andrew et al. (2006) Corneal toxicity of cell-penetrating peptides that inhibit Herpes simplex virus entry. J Ocul Pharmacol Ther 22:279-89

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