The original and all subsequent potent antivirals for treating herpes simplex virus (HSV) have been nucleosides. In addition to limited activity, they all share cross resistance. BAY 57-1293 is a helicase primase inhibitor that is more potent and may be safer than acyclovir, but it is almost untested in the eye. Acyclovir prevents only 40 - 50% of recurrences of HSV, and no topical agent prevents recurrences.
In Specific Aim 1, topical and systemic BAY 57-1293 will be compared with acyclovir and trifluridine to determine its efficacy in models of epithelial keratitis, stromal keratitis, and iritis and to determine if BAY 57-1293 can prevent recurrences of herpes when administered both topically and systemically. A recombinant strain of McKrae HSV (McKrae-EGFP) that expresses a fluorescent green protein will be used. The sensitivity of using the green fluorescence to identify experimental lesions will be evaluated, especially in recurrent keratitis which may lack typical dendritic lesions. PCR makes it possible, for the first time, to correlate not only demographics, but also seropositivity and titers of antibody and the results of cell-mediated immunity testing, with HSV-1 DMA shedding. In our recent study of HSV DNA in tears and saliva, viral DNA was recovered from antibody-negative and antibody-positive persons. One question is: How valuable and reliable are the antibody tests? In Specific Aim 2, IgG and IgM antibodies, as well as cell-mediated immunity, will be correlated with the presence and frequency of shedding in human subjects; viral production in tears and saliva will also be correlated with age and ethnicity. This may permit the defining of risk factors for recurrence for people with previous disease and perhaps for people who need to be immunosuppressed or treated with corticosteroids.
In Specific Aim 3, the production of viral DNA in tears and saliva will be used as a surrogate to test drug efficacy in human subjects. Aspirin and COX-2 inhibitors suppress virus production and infection in rabbits and mice, but the cyclooxygenase system works somewhat differently in man. Acyclovir provides only incomplete protection against reinfection in man. If we find that aspirin and COX-2 inhibitors suppress virus production, this would provide a rationale for the expensive and extensive testing of these drugs against infection in man. If they are additive to or synergistic with acyclovir in suppressing viral DNA production, tests on human infection could almost certainly follow. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002672-30
Application #
7465367
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Kurinij, Natalie
Project Start
1978-02-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
30
Fiscal Year
2008
Total Cost
$337,822
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Kennedy, David P; Clement, Christian; Arceneaux, Richard L et al. (2011) Ocular herpes simplex virus type 1: is the cornea a reservoir for viral latency or a fast pit stop? Cornea 30:251-9
Clement, Christian; Bhattacharjee, Partha S; Kaufman, Herbert E et al. (2009) Heat-induced reactivation of HSV-1 in latent mice: upregulation in the TG of CD83 and other immune response genes and their LAT-ICP0 locus. Invest Ophthalmol Vis Sci 50:2855-61
Bhattacharjee, Partha S; Neumann, Donna M; Foster, Timothy P et al. (2008) Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1. Exp Eye Res 87:122-30
Bhattacharjee, Partha S; Neumann, Donna M; Foster, Timothy P et al. (2008) Effective treatment of ocular HSK with a human apolipoprotein E mimetic peptide in a mouse eye model. Invest Ophthalmol Vis Sci 49:4263-8
Hill, James M; Ball, Melvyn J; Neumann, Donna M et al. (2008) The high prevalence of herpes simplex virus type 1 DNA in human trigeminal ganglia is not a function of age or gender. J Virol 82:8230-4
Toma, Hassanain S; Murina, Andrea T; Areaux Jr, Raymond G et al. (2008) Ocular HSV-1 latency, reactivation and recurrent disease. Semin Ophthalmol 23:249-73
Kaufman, Herbert E; Varnell, Emily D; Gebhardt, Bryan M et al. (2008) Efficacy of a helicase-primase inhibitor in animal models of ocular herpes simplex virus type 1 infection. J Ocul Pharmacol Ther 24:34-42
Kaufman, Herbert E; Azcuy, Ann M; Varnell, Emily D et al. (2005) HSV-1 DNA in tears and saliva of normal adults. Invest Ophthalmol Vis Sci 46:241-7
Gebhardt, Bryan M; Varnell, Emily D; Kaufman, Herbert E (2005) Inhibition of cyclooxygenase 2 synthesis suppresses Herpes simplex virus type 1 reactivation. J Ocul Pharmacol Ther 21:114-20
Gebhardt, Bryan M; Varnell, Emily D; Kaufman, Herbert E (2004) Acetylsalicylic acid reduces viral shedding induced by thermal stress. Curr Eye Res 29:119-25

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