Herpes simplex virus (HSV) is the leading cause of blindness due to infectious disease in the United States, and affects approximately 500,000 people a year. Different strains of virus have distinctive virulence phenotypes, indicating that specific determinants in the virus affect disease severity. Virulence is a multigenic phenomenon and likely requires interactions between viral proteins and viral and host proteins. We and others have previously demonstrated that mixed infections with two HSV strains can cause more severe disease due to complementation or recombination. These results imply that at least two virulence determinants are involved in mixed infections and the identification of the determinants provides a way to identify components cooperating in virulence. We have previously identified a pair of HSV-1 strains, OD4 and CJ394, that caused more severe ocular disease and neurovirulence when mixed. Available evidence indicates OD4 and CJ394 are not deletion mutants, suggesting different alleles may be involved in the increased virulence seen when the viruses are mixed. RFLP mapping of the genomes of 4 virulent OD4/CJ394 recombinants suggested that the EcoR1 H fragment of OD4 might carry a virulence determinant. We have now shown that the cloned OD4 EcoR1 H fragment (US1 to US12 genes) can indeed transfer increased virulence to CJ394. The major goals of this proposal are to (1) use subclones of the OD4 EcoRI H fragment in marker transfer to map the regions involved, (2) to sequence the respective regions of both OD4 and CJ394, and (3) to identify the amino acids involved in the virulence differences using site directed mutagenesis. Information on the role of multiple virulence determinants and their interactions will be critical for improving prevention and treatment of ocular disease, the use of HSV based vectors for gene delivery, and attenuated HSV vaccines.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007336-07
Application #
2161445
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1987-09-30
Project End
1998-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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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
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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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