Antiviral Activity of Retrocyclin–2 in HSV–Keratitis

Abstract

Abstract: : Purpose: To determine if retrocyclin–2, an antiviral theta–defensin peptide, is protective in a model of HSV keratitis infection. Methods: Retrocyclin–2 was tested in a murine model of HSV–1 KOS keratitis. Pre and post exposure treatment regimens were used and blepharitis, stromal disease and vascularization were measured. IC₅₀ values vs. HSV–1 KOS were determined in yield reduction and virucidal assays. Viral titers were measured by plaque assay. Latency was tested by explant of trigeminal ganglia. Results: The IC₅₀ value of retrocyclin–2 was 3.5 micromolar, by viral yield reduction. Retrocyclin–2 was not virucidal, and employing it in vivo post–infection was ineffective at blocking ocular disease. Pre–incubation of virus with retrocyclin–2 significantly reduced all measures of ocular disease. Pretreating the viral inoculum with retrocyclin–2 reduced viral titers by 4–logs at 1 day post–infection, and also reduced the number of eyes with recoverable virus from 100% to 40%. The percent of ganglia with reactivatable virus was 100% for infections initiated by untreated HSV–1 KOS, and 20% for infections initiated with retrocyclin–2–treated inocula. RC106, an analog of retrocyclin–2 with markedly reduced anti–HSV properties in vitro, also manifested commensurately reduced antiviral properties in the in vivo model. Conclusions: Retrocyclin–2 was able to prevent the development of HSV–1 keratitis, reduce viral titers, and reduce latent infection when used prophylactically, but not when used alone for post–exposure therapy. Retrocylin–2 may be useful as a prophylactic agent to prevent primary HSV–1 infection or reduce its severity.

Keywords: herpes simplex virus • keratitis • antiviral drugs