Gamma interferon impedes the establishment of herpes simplex virus type 1 latent infection but has no impact on its maintenance or reactivation in mice

Abstract

Murine models of gamma interferon (IFN-gamma) deficiency demonstrate the role of this cytokine in attenuating acute herpes simplex virus (HSV) disease; however, the effect of IFN-gamma on the establishment and maintenance of neuronal latency and viral reactivation is not known. Using the IFN-gamma knockout (GKO) model of IFN-gamma deficiency and sensitive quantitative PCR methods, we show that IFN-gamma significantly reduces the ganglion content of latent HSV-1 in BALB/c mice, which in turn delays viral time to reactivation following UV irradiation. Similar effects were not seen in the C57BL/6 strain. These results indicate that IFN-gamma significantly attenuates latent HSV infection in the mouse model of ocular infection but has no impact on the maintenance of latency or virus reactivation.

FIG. 1

GKO (C57BL/6) and control mice survive acute ocular HSV-1 infection equally well. Seven GKO and 14 control mice were inoculated with 10⁵ PFU of HSV-1 by corneal scarification. Survival rates were not statistically different.

FIG. 2

GKO (BALB/c) mice were more susceptible to acute ocular HSV-1 infection compared with control mice. Groups of four GKO or BALB/c control mice each received either 10³, 10⁴, or 10⁵ PFU of HSV-1 by corneal scarification. Significantly more wild-type mice survived infection with 10³ PFU of HSV-1 compared with GKO BALB/c mice (P < 0.008, Wilcoxon test). Survival rates at higher inocula of HSV-1 were not statistically different.

FIG. 3

HSV-1 replicates in peripheral tissues equally well in BALB/c GKO and control mice. Furthermore, BALB/c GKO and control mice are equally susceptible to HSV-1 neuroinvasiveness. Mice were inoculated on day 0 with 10⁴ PFU of HSV-1. Each time point represents the geometric mean of the viral titers of the indicated tissues taken from three animals. Error bars represent standard error.

FIG. 4

HSV-1 replicates in and propagates to the central nervous system equally well in C57BL/6 GKO and control mice. Mice were inoculated on day 0 with 10⁵ PFU of HSV-1. Each time point represents the geometric mean of the viral titers of indicated tissues taken from five animals. Error bars represent standard error.

FIG. 5

The contents of latent HSV DNA in trigeminal ganglia were similar in GKO and control mice of both C57BL/6 and BALB/c backgrounds. Genome copies of HSV-1 were determined by a quantitative fluorescent PCR assay. Significant differences in geometric means (log₁₀) between ganglia of BALB/c GKO (3.5 ± 0.1) and BALB/c control mice (2.3 ± 0.2) were detected. Geometric means of HSV-1 genome copy numbers in ganglia of C57BL/6 GKO mice (3.6 ± 0.1) were not statistically different from those of control mice (3.8 ± 0.1).