Peripheral replication and latency reactivation kinetics of the non-neurovirulent herpes simplex virus type 1 variant 1716.
The terminal portion of the herpes simplex virus (HSV) genome long repeat region has been shown to contain a neurovirulence gene. Both HSV-1 and HSV-2 mutants deleted in this gene fail to cause central nervous system (CNS) disease in mice. The HSV-1 strain 17 variant 1716, which has a 759 bp deletion encompassing the gene, grows normally in tissue culture but fails to grow following intracerebral inoculation of mice. This paper demonstrates that 1716 is capable of peripheral replication in the footpads of mice. However, no acute replication of virus is detectable in dorsal root ganglia up to 10 days after footpad inoculation. These results imply that the replication defect in 1716 is not host-specific, but is tissue- and/or cell type-specific. Latency reactivation kinetics demonstrate that 1716 is capable of establishing a latent infection, but the kinetics of reactivation are significantly impaired compared to wild-type virus and are dose-dependent. Lack of acute ganglionic replication combined with impaired reactivation kinetics support the conclusion that a proportion of 1716 genomes initiate a lytic infection which then aborts, and a proportion enter the latent state. The results with 1716 imply that its inability to replicate in CNS and peripheral nervous system neurons is specific, and that the block in replication is beyond the stage of adsorption and entry. A prerequisite for any live attenuated HSV vaccine is an inability to initiate CNS involvement following peripheral inoculation. In this respect, 1716 has prototype vaccine potential with the proviso that a direct extrapolation is being made from mouse to man.
Robertson
L M
LM
MRC Virology Unit, Institute of Virology, Glasgow, U.K.
MacLean
A R
AR
Brown
S M
SM
D000818:Animals; D005069:Evaluation Studies as Topic; D014644:Genetic Variation; D051379:Mice; D008807:Mice, Inbred BALB C; D009417:Nerve Tissue / Q000382:microbiology*; D018139:Simplexvirus / Q000472:pathogenicity*; D014774:Virulence; D014775:Virus Activation; D014779:Virus Replication