Role for gamma interferon in control of herpes simplex virus type 1 reactivation

Abstract

Observation of chronic inflammatory cells and associated high-level gamma interferon (IFN-gamma) production in ganglia during herpes simplex type 1 (HSV-1) latent infection in mice (E. M. Cantin, D. R. Hinton, J. Chen, and H. Openshaw, J. Virol. 69:4898-4905, 1995) prompted studies to determine a role of IFN-gamma in maintaining latency. Mice lacking IFN-gamma (GKO mice) or the IFN-gamma receptor (RGKO mice) were inoculated with HSV-1, and the course of the infection was compared with that in IFN-gamma-competent mice with the same genetic background (129/Sv//Ev mice). A time course study showed no significant difference in trigeminal ganglionic viral titers or the timing of establishment of latency. Spontaneous reactivation resulting in infectious virus in the ganglion did not occur during latency in any of the mice. However, 24 h after the application of hyperthermic stress to mice, HSV-1 antigens were detected in multiple neurons in the null mutant mice but in only a single neuron in the 129/Sv//Ev control mice. Mononuclear inflammatory cells clustered tightly around these reactivating neurons, and by 48 h, immunostaining was present in satellite cells as well. The incidence of hyperthermia-induced reactivation as determined by recovery of infectious virus from ganglia was significantly higher in the null mutant than in control mice: 11% in 129/Sv//Ev controls, 50% in GKO mice (P = 0.0002), and 33% in RGKO mice (P = 0.03). We concluded that IFN-gamma is not involved in the induction of reactivation but rather contributes to rapid suppression of HSV once it is reactivated.

FIG. 1

Immunoperoxidase staining of HSV-1 antigen in trigeminal ganglion sections. (A) Acute HSV-1 trigeminal ganglion section 4 days after viral inoculation. (B) RGKO trigeminal ganglion section and (C and D) GKO trigeminal ganglion sections 24 h after hyperthermia-induced HSV-1 reactivation. (E) GKO trigeminal ganglion section 48 h after hyperthermia-induced reactivation. (F) Latent infection of a GKO mouse showing spontaneous HSV-1 reactivation. Magnifications, ×10 (A), ×20 (B and D), and ×40 (C, E, and F). Images were further enlarged in PhotoShop for presentation. The arrows in panel E indicate HSV-1 antigen in satellite and/or infiltrating cells.

FIG. 2

Time course of trigeminal ganglion (Tg) HSV-1 titers after inoculation of 129/Sv//Ev, GKO, and RGKO mice by the corneal route. Line segments show mean numbers of plaque-forming units (PFU) for each day. Symbols show individual mice with a horizontal offset to distinguish strains and a diagonal offset to distinguish identical points.

FIG. 3

ISH for HSV-1 LAT in representative ganglionic sections from 129/Sv//Ev (A), GKO (B), and RGKO (C) mice photographed under dark-field illumination. Magnification was done with a 10× objective, and images were further enlarged in PhotoShop for presentation.