Gamma interferon can block herpes simplex virus type 1 reactivation from latency, even in the presence of late gene expression.
Herpes simplex virus type 1 (HSV-1)-specific CD8+ T cells and the cytokine gamma interferon (IFN-gamma) are persistently present in trigeminal ganglia (TG) harboring latent HSV-1. We define "latency" as the retention of functional viral genomes in sensory neurons without the production of infectious virions and "reactivation" as a multistep process leading from latency to virion assembly. CD8+ T cells can block HSV-1 reactivation in ex vivo mouse TG cultures and appear to be the sole source of IFN-gamma in these cultures. Here we demonstrate that IFN-gamma alone can block HSV-1 reactivation in some latently infected neurons, and we identify points of intervention in the life cycle of the reactivating virus. Cell suspensions of TG that were latently infected with recombinant RE HSV-1 expressing enhanced green fluorescent protein from the promoter for infected cell protein 0 (ICP0) or glycoprotein C (gC) were depleted of endogenous CD8+ or CD45+ cells and cultured in the presence or absence of IFN-gamma. Our results demonstrate that IFN-gamma acts on latently infected neurons to inhibit (i) HSV-1 reactivation, (ii) ICP0 promoter activity, (iii) gC promoter activity, and (iv) reactivation in neurons in which the ICP0 or gC promoter is active. Interestingly, we detected transcripts for ICP0, ICP4, and gH in neurons that expressed the ICP0 promoter but were prevented by IFN-gamma from reactivation and virion formation. Thus, the IFN-gamma blockade of HSV-1 reactivation from latency in neurons is associated with an inhibition of the expression of the ICP0 gene (required for reactivation) and a blockade of a step that occurs after the expression of at least some viral structural genes.
Decman
Vilma
V
University of Pittsburgh, Department of Ophthalmology, 203 Lothrop Street, Pittsburgh, PA 15213, USA.
Kinchington
Paul R
PR
Harvey
Stephen A K
SA
Hendricks
Robert L
RL
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D005260:Female; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D017874:Immediate-Early Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D044767:Ubiquitin-Protein Ligases; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D017874:Immediate-Early Proteins; D007371:Interferon-gamma; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1