Acyclovir Blocks Cytokine Gene Expression in Trigeminal Ganglia Latently Infected with Herpes Simplex Virus Type 1

Abstract

We have previously found that interleukin (IL)-2, IL-10, interferon (IFN)-gamma, RANTES, and tumor necrosis factor (TNF)-alpha mRNA transcription remain elevated in the trigeminal ganglia (TG) of herpes simplex virus type 1 (HSV-1) latently infected mice up to 120 days postinoculation (p.i.). To determine if this phenomenon was dependent on HSV-1 DNA replication after the establishment of latency (i.e., reactivation), cytokine gene expression was compared in TG of acyclovir-treated and untreated latently infected mice. Oral acyclovir treatment (begun 16 days p.i.) had no effect on serum levels of total anti-HSV-1 antibodies. However, there was a significant reduction in the titer of antibody specific for glycoprotein D and glycoprotein B but not glycoprotein H/L 120 days PI in the acyclovir-treated compared to vehicle-treated mice. These differences were not significant at earlier time points (i.e., days 34 and 60 p.i.). Consistent with these findings, acyclovir had no effect on cytokine gene expression in latently infected TG 35 and 60 days p.i. However, 120 days p.i., IFN-gamma and TNF-alpha mRNA were approaching baseline levels in TG of acyclovir-treated mice, but remained significantly elevated in untreated controls (i.e., IFN-gamma mRNA levels were sixfold higher in TG of untreated mice). Therefore, viral DNA replication appears to provide an antigenic stimulus for persistent cytokine gene expression in latently infected TG.

Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2

“…2). These data and other reports of early induction of TNF expression in tissues targeted by HSV-1 are consistent with a protective role for TNF in HSV-1 infection (11,27,28,41,60). Additionally, intraperitoneal injection of TNF 4 h before or 8 h after intraperitoneal HSV-1 inoculation of C57BL/6 mice significantly extended their survival rate compared to that for untreated C57BL/6 mice (55).…”

“…Accumulation of T cells, particularly CD8 ϩ T cells, was delayed and occurred coincident with the clearance of HSV-1 antigen from the ganglion. We and others previously reported the unexpected observation that the inflammatory response persisted well into latency, with associated production of IFN-␥ and TNF in close juxtaposition with infected neurons (11,27,41,59). In one study, TNF was the major cytokine produced in the ganglion and the only cytokine detected on the CNS side of the dorsal root entry zone (60).…”

Cytokine production in the nervous system of mice during acute and latent infection with herpes simplex virus type 1.

“…We believe this to be the first report of TNF-α production in the normal TG, although mRNA for this cytokine has previously been demonstrated in such tissue (Halford et al, 1996) ; hence this pleiotropic cytokine may be involved in homeostasis in the PNS. It is therefore noteworthy that many neurons in the normal ganglion constitutively express TNF receptors (Cunningham et al, 1997).…”

CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection

“…Frozen stocks were diluted in RPMI 1640 medium immediately prior to use. Plaque assays using African green monkey kidney fibroblasts (Vero cells, ATCC CCL-81, American Type Tissue Culture Collection, Manassas, VA) were performed in RPMI-1640 medium supplemented with 10% FBS (Invitrogen, Calsbad, CA), gentamicin (Invitrogen), and antibiotic-antimycotic solution (Invitrogen) at 37° C, 5% CO 2 , and 95% humidity as previously described [45].…”