Transdominant inhibition of herpes simplex virus growth in transgenic mice.
A mutant allele (X25) of an essential regulatory protein, ICP4, encoded by herpes simplex virus (HSV) has been shown to have a transdominant, negative effect on the activity of the wild-type protein, resulting in the inhibition of virus growth in vitro. The X25 protein appears to exert its transdominant effect by sequestering functional ICP4 monomers into nonfunctional, heterodimeric complexes (A. Shepard, P. Tolentino, and N. A. DeLuca, 1990, J. Virol. 64, 3916-3926). In order to assess the antiviral potential of X25 in vivo, four transgenic mouse lines were generated bearing 1 to 10 copies of a DNA fragment encoding the mutant allele. Monolayers of embryonic cells prepared from each of the lines expressed the transgenic X25 protein. When challenged via the eye, every line exhibited at least some enhanced resistance to HSV infection. In the best line, transgenic animals exhibited a statistically significant (> 95% confidence) 5- to 13-fold lower eye swab titer relative to their nontransgenic littermates at Day 1 postinfection. A similar reduction in titer was observed in the trigeminal ganglia at Day 3 postinfection. These results indicate that the X25 protein is able to exert a significant antiviral effect in vivo.
Smith
C A
CA
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115.
DeLuca
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NA
D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000382:microbiology; D015967:Gene Expression Regulation, Viral; D005799:Genes, Dominant; D017874:Immediate-Early Proteins; D007113:Immunity, Innate; D051379:Mice; D008822:Mice, Transgenic / Q000382:microbiology*; D018139:Simplexvirus / Q000235:genetics* / Q000254:growth & development* / Q000472:pathogenicity; D015533:Transcriptional Activation; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics*; D014774:Virulence
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D054334:Viral Regulatory and Accessory Proteins; C048925:herpes simplex virus, type 1 protein ICP4