A herpes simplex virus ribonucleotide reductase deletion mutant is defective for productive acute and reactivatable latent infections of mice and for replication in mouse cells.
Herpes simplex virus encodes a ribonucleotide reductase that is not essential for virus growth in dividing cells at 37 degrees. This enzyme has been proposed as a target for antiviral drugs; its utility in this regard could depend upon its importance in vivo. To test the requirement of viral ribonucleotide reductase in a mammalian host, we tested a mutant virus, lacking most of the gene encoding the ribonucleotide reductase large subunit, in a mouse eye model of pathogenesis and latency where the wild-type virus establishes reactivatable latent infections in trigeminal ganglia following corneal inoculation. The deletion mutant was severely impaired in its ability to replicate acutely in the eye and in the trigeminal ganglion and failed to establish reactivatable latent infections. In contrast, a recombinant virus in which the deleted sequences were restored was competent for both acute and latent infections. The defects of the deletion mutant in the mouse may be related to its severely impaired growth at 38 degrees in mouse cells relative to its growth in Vero cells. These results indicate that ribonucleotide reductase is critical for productive acute and reactivatable latent infections in mice and replication in mouse cells at 38 degrees and suggest that caution be exercised in extrapolating from studies conducted in mice to human infections when judging the utility of this enzyme as a target for antiviral chemotherapy.
Jacobson
J G
JG
Committee on Virology, Harvard Medical School, Boston, Massachusetts 02115.
Leib
D A
DA
Goldstein
D J
DJ
Bogard
C L
CL
Schaffer
P A
PA
Weller
S K
SK
Coen
D M
DM
D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005123:Eye / Q000382:microbiology; D005724:Ganglia / Q000382:microbiology; D007635:Keratitis, Dendritic / Q000382:microbiology*; D051379:Mice; D009154:Mutation; D012008:Recurrence; D012264:Ribonucleotide Reductases / Q000235:genetics*; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D014709:Vero Cells; D014779:Virus Replication
D012264:Ribonucleotide Reductases