Construction and characterization of a recombinant herpes simplex virus type 1 which overexpresses the transrepressor protein ICPOR.
ICPOR is a truncated form of the herpes simplex virus type 1 (HSV-1) transactivator protein ICPO that is synthesized at low levels during infection through an alternative splicing mechanism. In transient expression assays, ICPOR has been shown to inhibit the transactivation function of several HSV-1 regulatory proteins, suggesting that an antiviral strategy which alters normal ICPO mRNA splicing and thereby stimulates the synthesis of ICPOR protein may have potential in suppressing HSV-1 infections. To explore the feasibility of this approach, a recombinant virus was constructed which expressed high levels of ICPOR instead of ICPO. Surprisingly, overexpression of the ICPOR protein in this virus, HSV-KST, had no detectable effect on virus replication, since the growth properties of HSV-KST were indistinguishable from those of the ICPO/ICPOR null mutant dl 1403, and HSV-KST was no more efficient than dl 1403 at inhibiting the replication of an ICPO-expressing wild-type virus. The absence of a demonstrable phenotype in HSV-KST was not due to the acquisition of an inactivating mutation in the gene encoding ICPOR, since copies of the gene rescued from this virus retained full transrepression capability in transient expression assays. These results indicate that the ability of ICPOR to act as a transrepressor is significantly reduced if not completely eliminated in the context of a productive HSV-1 infection and suggest that this protein may not represent an exploitable target for the development of novel antiviral therapies.
Spatz
S J
SJ
Infectious Disease Section, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Nordby
E C
EC
Weber
P C
PC
D017398:Alternative Splicing; D000818:Animals; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D005240:Feasibility Studies; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D011995:Recombination, Genetic; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases; D014709:Vero Cells; D014779:Virus Replication
D017874:Immediate-Early Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1