Gamma interferon can prevent herpes simplex virus type 1 reactivation fromlatency in sensory neurons

We recently demonstrated that CD8(+) T cells could block herpes simplex vir us type 1 (HSV-1) reactivation from latency in ex vivo trigeminal ganglion (TG) cultures without destroying the infected neurons. Here we establish th at CD8(+) T-cell prevention of HSV-1 reactivation from latency is mediated at least in part by gamma interferon (IFN-gamma). We demonstrate that IFN-g amma was produced in ex vivo cultures of dissociated latently infected TG b y CD8(+) T cells that were present in the TG at the time of excision. Deple tion of CD8(+) T cells or neutralization of IFN-gamma significantly enhance d the rate of HSV-1 reactivation from latency in TG cultures. When TG cultu res were treated with acyclovir for 4 days to insure uniform latency, suppl ementation with recombinant IFN-gamma blocked HSV-1 reactivation in 80% of cultures when endogenous CD8(+) T cells were present and significantly redu ced and delayed HSV-1 reactivation when CD8(+) T cells or CD45(+) cells wer e depleted from the TG cultures. The effectiveness of recombinant IFN-gamma in blocking HSV-1 reactivation was lost when its addition to TG cultures w as delayed by more than 24 h after acyclovir removal. We propose that when the intrinsic ability of neurons to inhibit HSV-1 gene expression is compro mised, HSV-specific CD8(+) T cells are rapidly mobilized to produce IFN-gam ma and perhaps other antiviral cytokines that block the viral replication c ycle and maintain the viral genome in a latent state.