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Y. Gordon, K. A. Yates, E. G. Romanowski; ddC Inhibits Wild Type and ddC-Resistant Ad5 in the Ad5/NZW Rabbit Ocular Model. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5988.
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There remains an unfulfilled need for an effective antiviral to treat adenovirus (Ad) ocular infections worldwide. However, the emergence of viral resistance to an antiviral might limit its usefulness and alter viral pathogenicity. 2',3'-dideoxycytidine (ddC) is a nucleoside analog that demonstrates potent anti-Ad activity in vitro. We created an Ad5 ddC-resistant mutant in vitro that was 56 fold more resistant to ddC than the parental wild type (wt) virus. The goals of the current study were to 1) determine whether ddC would demonstrate anti-Ad activity in vivo against a wt Ad5, 2) whether in vitro ddC resistance altered in vivo pathogenesis, and 3) whether in vitro ddC resistance could be overcome in vivo.
20 NZW rabbits were topically inoculated in both eyes, following corneal scarification, with 1.4 x 106 pfu/eye of Ad5 ATCC wt virus (ddC IC50 = 0.08 µg/ml) or the Ad5 ddC-resistant mutant (ddC IC50 = 4.5 µg/ml). On day 1, the rabbits from each virus group were subdivided into 2 topical treatment groups (n=10/group): I - 2% ddC; II - Control (saline). The rabbits were treated in both eyes QID for 7 days. All eyes were cultured for virus on days 0, 1, 3, 4, 5, 7, 9, 11, and 14.
* p < 0.005 Compared to specific virus Control. p < 0.001 compared to Ad5 ddC-res mut/Control.
2% ddC effectively inhibited Ad replication in the Ad5/NZW rabbit model. The in vitro selection for ddC-resistance in the Ad5 parental virus was associated with increased ocular pathogenicity in vivo. In vitro ddC resistance was overcome in vivo by the dose regimen of ddC.
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