Antisense–Oligonucleotides Targeting Tumor Necrosis Factor–Alpha in Murine Herpes Simplex Virus Type 1 Retinitis

Abstract

Abstract: : Purpose: Injection of herpes simplex virus (HSV)–1 into the anterior chamber (AC) of one eye is followed by ipsilateral iritis and contralateral retinitis (HSV–R). This study investigated whether topical tumor necrosis factor–alpha (TNF–alpha)–antisense–oligonucleotide (ASON) treatment might affect the course of HSV–R. Methods: Influence of TNF–alpha–ASON and sequence–unspecific control (C) ON on the TNF–alpha–expression from regional lymph node (rLN) cells was analyzed in vitro by ELISA. In vivo uptake was determined after parabulbar (p.b.) injection of FITC–labeled TNF–alpha–ASON. BALB/c mice were injected in the AC of the right eyes with HSV–1 (KOS); the left eyes were injected p.b. 3 times with TNF–alpha–ASON; CON or buffer. The clinical course of HSV–R, ocular inflammatory cell–infiltration, uptake of [3H]thymidine from rLN cells and viral replication in the eyes were analyzed. Results: TNF–alpha–ASON reduced the cytokine expression in vitro. In vivo, FITC–TNF–alpha–ASON was found in the choroid and retina up to 7 days after injection. TNF–alpha–ASON injection reduced the early inflammatory cell infiltration in the choroid and retina of the treated eye, and decreased the HSV–1 specific [3H]thymidine uptake from rLN cells. On a later time point, the virus titers, inflammatory cell infiltration and HSV–R had increased in the TNF–alpha–ASON treated eyes. Conclusions: TNF–alpha–ASON reduced the lymphocytic cytokine secretion in vitro. Topical TNF–alpha–ASON–injection reduced early ocular inflammatory cell infiltration, but delayed the virus clearance and increased the severity of HSV–R in the treated eyes.

Keywords: herpes simplex virus • uveitis-clinical/animal model • inflammation