The probability of in vivo reactivation of herpes simplex virus type 1 increases with the number of latently infected neurons in the ganglia

Abstract

The purpose of this study was to define the relationship between herpes simplex virus (HSV) latency and in vivo ganglionic reactivation. Groups of mice with numbers of latently infected neurons ranging from 1.9 to 24% were generated by varying the input titer of wild-type HSV type 1 strain 17syn+. Reactivation of the virus in mice from each group was induced by hyperthermic stress. The number of animals that exhibited virus reactivation was positively correlated with the number of latently infected neurons in the ganglia over the entire range examined (r = 0.9852, P < 0. 0001 [Pearson correlation]).

FIG. 1

The percentage of mice undergoing viral reactivation following HS. Groups of latently infected mice inoculated with the input titers indicated were subjected to HS. Shown are the numbers of mice exhibiting viral reactivation over the total number treated. There was no difference between the two groups receiving input titers of >10⁵ PFU (two-sided P = 0.7, Fisher’s exact test). For statistical analysis, these two groups were combined and compared to the groups receiving either 2 or 3 logs less input virus. The differences were significant (P = 0.04 and P < 0.0001, respectively, Fisher’s exact test).

FIG. 2

The percentage of neurons latently infected and the percentage of mice that exhibited HSV reactivation following HS in ACV- and sham-treated groups. The percentage of latently infected neurons in ganglia of sham-treated mice and mice which had been treated with ACV from the time of inoculation (ACV₀) or from 36 h postinoculation (ACV₃₆) through day 7 postinoculation was determined by CXA-D. Viral reactivation was induced in mice from each of these groups. The differences between the number of latently infected neurons and the number of mice exhibiting reactivation in the sham- and ACV-treated groups were both significant (two-tailed P < 0.0001 for both ACV treatment groups, Fisher’s exact test).

FIG. 3

Plot of the number of latently infected neurons per TG pair versus the percentage of mice exhibiting reactivation. Data from both the input-titer experiment and the ACV experiment were included. The number of latently infected neurons per TG pair was determined from the PIN for each input titer group. There is a significant correlation between these two variables (r = 0.9852, P < 0.0001 [Pearson correlation test]).