Use of immunostimulatory sequence-containing oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection

Richard Pyles, Debbie Higgins, Claudia Chalk, Anthony Zalar, Joseph Eiden, Carrie Brown, Gary Van Nest, Lawrence R. Stanberry

Research output: Contribution to journalArticle

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Abstract

Synthetic oligonucleotides containing CpG motifs in specific sequence contexts have been shown to induce potent immune responses. We have evaluated mucosal administration of two immunostimulatory sequence (ISS)-containing phosphorothioate-stabilized oligonucleotides for antiherpetic efficacy in animal models. The ISS oligonucleotides, suspended in phosphate-buffered saline, were tested in mouse and guinea pig vaginal models of herpes simplex virus type 2 (HSV-2) infection. For comparison, groups of untreated, non-ISS oligonucleotide-treated, and acyclovir-treated animals also were monitored. The results indicated that vaginal epithelial application of ISS (up to 6 h after viral inoculation) with mice lethally challenged with HSV-2 delayed disease onset and reduced the number of animals that developed signs of disease (P = 0.003). ISS application significantly increased survival rates over those of controls (P = 0.0014). The ISS also impacted an established infection in the guinea pig model of HSV-2 disease. A single administration of ISS (21 days after viral inoculation) significantly reduced the frequency and severity of HSV-2 lesions compared to results with non-ISS oligonucleotide-treated and untreated guinea pigs (P < 0.01). HSV-2 is shed from the vaginal cavity of the guinea pig in the absence of lesions, similar to the case with humans. As an additional indication of ISS efficacy, the magnitude of viral shedding also was significantly reduced in ISS-treated animals (P < 0.001). These effects appeared to be immunologically mediated, since ISS had no direct effect on HSV-2 replication in vitro using standard plaque assays. These data suggest that ISS may be useful in the treatment and control of genital herpes in humans.

Original languageEnglish (US)
Pages (from-to)11387-11396
Number of pages10
JournalJournal of Virology
Volume76
Issue number22
DOIs
StatePublished - 2002

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Human herpesvirus 2
Herpes Genitalis
Human Herpesvirus 2
Virus Diseases
oligonucleotides
Oligonucleotides
genitalia
guinea pigs
Guinea Pigs
infection
lesions (animal)
Mucosal Administration
Therapeutics
Phosphorothioate Oligonucleotides
Virus Shedding
animals
viral shedding
Acyclovir
mice
Virus Replication

ASJC Scopus subject areas

  • Immunology

Cite this

Use of immunostimulatory sequence-containing oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection. / Pyles, Richard; Higgins, Debbie; Chalk, Claudia; Zalar, Anthony; Eiden, Joseph; Brown, Carrie; Van Nest, Gary; Stanberry, Lawrence R.

In: Journal of Virology, Vol. 76, No. 22, 2002, p. 11387-11396.

Research output: Contribution to journalArticle

Pyles, Richard ; Higgins, Debbie ; Chalk, Claudia ; Zalar, Anthony ; Eiden, Joseph ; Brown, Carrie ; Van Nest, Gary ; Stanberry, Lawrence R. / Use of immunostimulatory sequence-containing oligonucleotides as topical therapy for genital herpes simplex virus type 2 infection. In: Journal of Virology. 2002 ; Vol. 76, No. 22. pp. 11387-11396.
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abstract = "Synthetic oligonucleotides containing CpG motifs in specific sequence contexts have been shown to induce potent immune responses. We have evaluated mucosal administration of two immunostimulatory sequence (ISS)-containing phosphorothioate-stabilized oligonucleotides for antiherpetic efficacy in animal models. The ISS oligonucleotides, suspended in phosphate-buffered saline, were tested in mouse and guinea pig vaginal models of herpes simplex virus type 2 (HSV-2) infection. For comparison, groups of untreated, non-ISS oligonucleotide-treated, and acyclovir-treated animals also were monitored. The results indicated that vaginal epithelial application of ISS (up to 6 h after viral inoculation) with mice lethally challenged with HSV-2 delayed disease onset and reduced the number of animals that developed signs of disease (P = 0.003). ISS application significantly increased survival rates over those of controls (P = 0.0014). The ISS also impacted an established infection in the guinea pig model of HSV-2 disease. A single administration of ISS (21 days after viral inoculation) significantly reduced the frequency and severity of HSV-2 lesions compared to results with non-ISS oligonucleotide-treated and untreated guinea pigs (P < 0.01). HSV-2 is shed from the vaginal cavity of the guinea pig in the absence of lesions, similar to the case with humans. As an additional indication of ISS efficacy, the magnitude of viral shedding also was significantly reduced in ISS-treated animals (P < 0.001). These effects appeared to be immunologically mediated, since ISS had no direct effect on HSV-2 replication in vitro using standard plaque assays. These data suggest that ISS may be useful in the treatment and control of genital herpes in humans.",
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