Optic Neuritis in Different Strains of Mice by a Recombinant HSV-1 Expressing Murine Interleukin-2

Abstract

Purpose The authors have shown previously that a recombinant HSV-1 that constitutively expresses two copies of murine IL-2 (HSV-IL-2) induces demyelination by activated CD8+ T cells in the brain and spinal cord of ocularly infected female BALB/c mice. The present study was conducted to determine whether the ocular infection with this recombinant virus induces optic neuritis independent of virus dose, major histocompatibility complex (MHC) background, or sex. Methods Female BALB/c, C57BL/6, SJL/6, and 129SVE mice and male BALB/c mice were ocularly infected with different doses of recombinant HSV-IL-2 virus. Demyelination of optic nerves in infected mice was monitored histologically using Luxol fast blue staining and by measurement of visual-evoked cortical potentials (VECPs). Results Both focal and diffuse regions of demyelination of the optic nerves were observed in the HSV-IL-2–infected mice as early as day 10 after infection and as late as day 60 after infection (the final experimental time point) in all strains of mice tested. Optic nerve demyelination was not observed in control mice ocularly infected with HSV-IL-4 or wild-type HSV-1. VECP responses were delayed significantly in the HSV-IL-2–infected mice compared with mice infected with control viruses. Conclusions The results demonstrate for the first time that a combination of viral infection and constitutive expression of IL-2, but not IFN-γ or IL-4, can result in demyelination and visual impairment in the optic nerves of ocularly infected mice.

Role of Interleukin-2 and Herpes Simplex Virus 1 in Central Nervous System Demyelination in Mice

“…1. Consistent with the results obtained when mice were infected with HSV-IL-2 (18)(19)(20)24), administration of murine IL-2 using an implanted miniature osmotic pump and ocular infection with wt HSV-1 induced demyelination in the ON, SC, and brain of all mice tested (Fig. 1A, rIL-2 protein ϩ HSV-1) but was not observed in mice treated with murine IL-2 in the absence of ocular infection (Fig.…”

“…Demyelination was detected in the CNS of mice that received IL-2 by using rIL-2 protein, IL-2 DNA, or IL-2 peptides. Similar to our findings in our previous study (18), we detected CNS demyelination in BALB/c and C57BL/6 mouse strains. In addition, CNS demyelination was detected in both strains of mice infected with virulent wt HSV-1 strain McKrae and avirulent wt HSV-1 strain KOS.…”

“…Our published data establish that ocular infection of mice with HSV-IL-2 elicits demyelination of the optic nerve, spinal cord, and brain (18)(19)(20)24). In these studies, we looked at the time course of appearance of demyelination in mice infected with HSV-IL-2 (18)(19)(20)24).…”

“…Previously, to show the involvement of higher levels of IL-2 in combination with viral infection in CNS demyelination, we constructed a recombinant HSV-1 strain constitutively expressing mIL-2, referred to as HSV-IL-2 (13). We have shown that infection of different strains of mice with the HSV-IL-2 recombinant resulted in CNS demyelination (17,18). We have also found that infection of mice with a recombinant HSV-1 expressing IL-12p70 or injection of mice with IL-12p70 DNA blocks the CNS demyelination induced by the HSV-IL-2 recombinant (19,20).…”

“…Using these viruses, we have shown that infection of different strains of mice with a recombinant HSV-1 strain constitutively expressing IL-2 (HSV-IL-2), but not HSV-IL-4, HSV-IFN-␥, HSV-IL-12p35, or HSV-IL12p40, results in demyelination of the optic nerves (ONs), the spinal cords (SCs), and the brains of the infected mice, as determined by histologic examination of tissues obtained at necropsy (17,18). In addition, the HSV-IL-2-infected mice developed optic neuropathy, as determined by changes in the visual evoked cortical potentials (VECPs) (18). Using knockout mice, depletion, and transfer studies, we found that both CD8 ϩ and CD4 ϩ T cells contributed to HSV-IL-2-induced central nervous system (CNS) demyelination, with CD8 ϩ T cells being the primary inducers (19).…”