HSV1 strain sensitivity in experimental rabbit keratitis: evolution under repeated topical IDU administrations.

Area of Science:

• Ophthalmology
• Virology
• Pharmacology

Background:

• Herpes simplex virus type 1 (HSV1) infections can lead to ocular complications.
• Antiviral drug resistance is a significant challenge in managing recurrent HSV infections.

Purpose of the Study:

• To investigate the development of HSV1 resistance to topical idoxuridine (IDU) following repeated administration in a rabbit model.
• To assess cross-resistance to acyclovir (ACV) and other antiviral agents.
• To correlate in vitro resistance markers with in vivo pathogenicity.

Main Methods:

• Serial topical administration of IDU to rabbits over 6 passages (P1-P6).
• Clinical assessment of corneal ulcer healing and viral shedding.
• In vitro plaque reduction assays and dye-uptake assays to determine drug efficacy (ED50, ED90).
• Measurement of viral thymidine kinase (TK) activity.

Main Results:

• Delayed ulcer cicatrization observed from P2, with complete clinical resistance by P3.
• Cross-resistance to acyclovir (ACV) demonstrated by P7.
• In vitro assays predicted resistance early via increased ED90 values.
• HSV isolates showed cross-resistance to TK-dependent drugs, with reduced TK activity, but maintained sensitivity to Ara-A and PFA.
• Drug-resistant HSV exhibited unrestricted corneal pathogenicity.

Conclusions:

• Repeated topical IDU induces HSV1 resistance and cross-resistance to ACV in vivo.
• In vitro methods can predict antiviral resistance development.
• HSV resistance impacts viral pathogenicity and necessitates careful monitoring of drug efficacy.