Heat-Induced Reactivation of HSV-1 in Latent Mice: Upregulation in the TG ofCD83and Other Immune Response Genes and Their LAT-ICP0 Locus

Abstract

To determine changes in host gene expression in HSV-1 latent trigeminal ganglia (TG) after hyperthermic stress. Scarified corneas of 6-week-old female BALB/c mice were inoculated with either HSV-1 17Syn(+) (high phenotypic reactivator) or 17DeltaPst(LAT(-)) (low phenotypic reactivator) at 10(4) plaque-forming units/eye. At 28 days after infection, viral reactivation was induced in some of the infected mice with hyperthermic stress, and the mice were killed after 1 hour. Heat-treated uninfected mice served as the control. Labeled cRNA derived from TG-isolated total RNA was hybridized to 430 2.0 chips containing 14,000 mouse genes. Gene expression was confirmed by quantitative real-time PCR. There was no difference in gene expression in the non-heat-treated mice. Gene expression in the TG of each of the heat-treated mouse groups (17Syn(+), 17DeltaPst(LAT(-)) and uninfected) yielded upregulation of more than twofold of a group of the same genes, designated as heat stress-induced gene expression. Twenty-nine genes (0.2%) were significantly upregulated (2- to 17-fold) when the heat stress-induced gene expression was subtracted from the gene expression of 17Syn(+) latent TG relative to 17DeltaPst(LAT(-)) latent TG 1 hour after mouse hyperthermic stress. Nine host adaptive immunity genes comprising Ig molecules, CD83, CD8A, ADA, and CCL8 were the largest subset upregulated, and all were confirmed by real-time PCR. Others identified included genes involved in hypothalamic-pituitary gland functions. Hyperthermic stress-induced reactivation of the HSV-1 high phenotypic reactivator can upregulate gene expression involved in B-cell function and in T-cell function. CD83 is implicated in HSV-1 latency, suggesting it could also be involved in immune-mediated mechanisms of viral reactivation.