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M.P. Langford, J.G. Abrams, T.B. Redens, D.E. Texada, M.I. Muggeridge; Comparison of the Antiviral Activity of Acivicin (AT125) Against Herpesvirus Infection in Human Lens and –Glutamyltranspeptidase Positive Conjunctival Cells . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2793.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To compare the antiviral efficacy of the glutamine (Gln) analog acivicin (AT125) [i.e., an inhibitor of intracellular Gln utilized for CTP synthesis and a non–reversible inhibitor of the generation of extracellular glutamate (Glu) from Gln and glutathione by γ–glutamyltranspeptidase (GGT)] against herpesvirus (HSV) infection in conjunctival (strongly GGT positive) and lens cells (low levels of GGT activity). Methods: HSV–1 (strains S17, KOS, McKrae and F1) and HSV–2 (strains 186 and 333) yields in cultures of Chang’s human conjunctival cells (HCC) and human lens epithelial cells (HLEC) treated with and without different concentrations of AT125 were compared by plaque assay. The GGT activity (i.e., one unit equals the conversion of 1 nanomole of L–γ–glutamyl–p–nitroanalide/hr) was determined for HCC and HLEC. Results: The 50% inhibitory dose (ID50) of AT125 against HSV–1 and HSV–2 (0.5–1 µM) in HCC was up to 100–fold lower than in HLEC (60–100 µM). AT125 at 10 µM reduced HSV–1 yields by 2.4 ±1.2 log10 units in HCC and by 1.4 ±0.6 log10 units in HLEC. Concomitantly, 10 µM AT125 reduced HSV–2 yields by 3.9± 0.3 log10 units in HCC and HLEC. HSV–1 S17 and HSV–2 186 tended to be more sensitive to AT125 than the other HSV strains tested. The GGT activity of HCC cultures (3,477±678 U/culture) was inhibited >50% at 24 h post incubation with 0.3 µM AT125. GGT activity was undetectable in HLEC cultures (<10 U/culture). Conclusions: The inhibition of HSV infection by AT125 was greater in HCC than in HLEC cells. AT125 inhibited HSV–2 replication (known to require Gln) to a greater extent than HSV–1. The higher sensitivity of HSV–1 to AT125 in GGT positive HCC cells than in HLEC suggests that the Glu generated from Gln by GGT activity is utilized by HSV infected GGT positive cells and may constitute an important tissue and virus–specific antiviral target against HSV infection.
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