The long-term objectives of this project are to elucidate the mechanism of Herpes simplex virus (HSV) infection and to eliminate the recurrent infections that result from reactivation of latent virus.
The specific aims of the proposal are to: (1) characterize neurons from the trigeminal ganglia according to various parameters which may be correlated with permissiveness or resistance to infection with HSV; (2) develop markers which can identify the presence of latent HSV; (3) improve treatment for acute and recurrent HSV infection by identification and development of new and/or improved biological and chemical antiviral agents such as interferons, nucleoside analogs, etc.; and (4) develop a non-human primate ocular model of recurrent HSV infection to study all of the above in a model that is closer to the human condition than the animal models previously studied. The health relatedness of the project is clear because an estimated 300,000 new cases of herpetic keratitis are reported in the United States each year. Latent virus becomes established in neurons that innervate the cornea; repeated spontaneous reactivation of the latent virus occurs in 25-50% of cases within two years and subsequent recurrences frequently leads to additional damage of ocular tissue with the increased risk of blindness. Better treatment of infections, inhibition of virus reactivation or eradication of latent virus from the neurons would eliminate the problems resulting from herpes virus. At present, numerous topical treatment regimens can reduce severity of ocular involvement but recurrences cannot be prevented and HSV cannot be eradicated from the nervous system. The methodology to be used to achieve the specific aims of this proposal include basic virus isolation procedure in addition to a combination of molecular, immunofluorescent and radiolabelled probes and immunocytochemical techniques using monoclonal antibodies, labelled lectins and horseradish peroxidase tracking with light and electron microscopy to identify latent HSV and the neuronal cells in which the virus establishes itself. Other techniques involve chemical reactivation of latent HSV concurrent with antiviral drug treatment to eradicate latent virus, use of neuron cell cultures as in vitro models of acute and latent infection. Additional specific methods to be used include, DNA hybridization, southern blotting, gel electrophoresis, immunoblot and radioimmunoprecipitation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002957-11
Application #
3257268
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1979-04-01
Project End
1992-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
11
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Doheny Eye Institute
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Das, A; Trousdale, M D; Ren, S et al. (1999) Inhibition of herpes simplex virus type 1 and adenovirus type 5 by heterocyclic Schiff bases of aminohydroxyguanidine tosylate. Antiviral Res 44:201-8
Trousdale, M D; Nobrega, R; Stevenson, D et al. (1995) Role of adenovirus type 5 early region 3 in the pathogenesis of ocular disease and cell culture infection. Cornea 14:280-9
Hui, M B; Lien, E J; Trousdale, M D (1994) Inhibition of human adenoviruses by 1-(2'-hydroxy-5'-methoxybenzylidene)amino-3-hydroxyguanidine tosylate. Antiviral Res 24:261-73
Brooks, S E; Kaza, V; Nakamura, T et al. (1994) Photoinactivation of herpes simplex virus by rose bengal and fluorescein. In vitro and in vivo studies. Cornea 13:43-50
Trousdale, M D; Goldschmidt, P L; Nobrega, R (1994) Activity of ganciclovir against human adenovirus type-5 infection in cell culture and cotton rat eyes. Cornea 13:435-9
Trousdale, M D; Law, J L; Yarber, F A et al. (1992) Evaluation of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-ethyluracil in a rabbit model of herpetic keratitis. Antiviral Res 17:157-67
Tsai, J C; Garlinghouse, G; McDonnell, P J et al. (1992) An experimental animal model of adenovirus-induced ocular disease. The cotton rat. Arch Ophthalmol 110:1167-70
Cote, M A; Irvine, J A; Rao, N A et al. (1991) Evaluation of the rabbit as a model of Acanthamoeba keratitis. Rev Infect Dis 13 Suppl 5:S443-4
McDonnell, P J; Kwitko, S; McDonnell, J M et al. (1991) Characterization of infectious crystalline keratitis caused by a human isolate of Streptococcus mitis. Arch Ophthalmol 109:1147-51
Trousdale, M D; Steiner, I; Spivack, J G et al. (1991) In vivo and in vitro reactivation impairment of a herpes simplex virus type 1 latency-associated transcript variant in a rabbit eye model. J Virol 65:6989-93

Showing the most recent 10 out of 19 publications