NEURON-SPECIFIC RESTRICTION OF A HERPES-SIMPLEX VIRUS RECOMBINANT MAPS TO THE UL5 GENE

Citation
Dc. Bloom et Jg. Stevens, NEURON-SPECIFIC RESTRICTION OF A HERPES-SIMPLEX VIRUS RECOMBINANT MAPS TO THE UL5 GENE, Journal of virology, 68(6), 1994, pp. 3761-3772
Citations number
30
Categorie Soggetti
Virology
Journal title
ISSN journal
0022538X
Volume
68
Issue
6
Year of publication
1994
Pages
3761 - 3772
Database
ISI
SICI code
0022-538X(1994)68:6<3761:NROAHV>2.0.ZU;2-L
Abstract
We have previously shown that, when compared with either parent, a her pes simplex virus type 1/herpes simplex virus type 2 intertypic recomb inant (R13-1) is attenuated by 10,000-fold with respect to neurovirule nce in mice. Despite this, after intracranial inoculation, R13-1 repli cated to titers of 10(5) PFU per brain. We present evidence that the r estriction is specific for replication in neurons and have taken a thr ee-step approach in determining the basis of the attenuation by (i) ch aracterizing cellular tropism of the virus in both central and periphe ral nervous systems, (ii) defining where in the viral replication cycl e the restriction is manifest, and (iii) identifying the genetic basis of the restriction through marker rescue analysis. Following inoculat ion into the animal, R13-1 viral antigens predominate in nonneuronal c ells, and the block to replication in neurons was found to be beyond t he level of adsorption and penetration. Despite the restricted replica tion within neurons, the virus established a latent infection in spina l ganglia and could be reactivated by in vitro cocultivation of the ga nglia. In studies carried out in cell culture, R13-1 was Pound to repl icate normally in mouse embryo fibroblasts and primary mouse glial cel ls but was restricted by 1,000-fold in primary mouse neurons and PC12 cells. R13-1 appeared to produce normal levels of early RNA in these t ells, but production of DNA and late RNA was less than that of the wil d type. Marker rescue analysis localized the fragment responsible for restoring neurovirulence to UL5, a component of the origin-binding com plex implicated in replication of the viral genome. Our results with t his virus, crith a cell-specific restriction, suggest that a neuron-sp ecific component is involved in viral replication.