Quantification of poly(I

C)-mediated protection against genital herpes simplex virus type 2 infection

Melissa M. Herbst-Kralovetz, Richard Pyles

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Alternative strategies for controlling the growing herpes simplex virus type 2 (HSV-2) epidemic are needed. A novel class of immunomodulatory microbicides has shown promise as antiherpetics, including intravaginally applied CpG-containing oligodeoxynucleotides that stimulate toll-like receptor 9 (TLR9). In the current study, we quantified protection against experimental genital HSV-2 infection provided by an alternative nucleic acid-based TLR agonist, polyinosine-poly(C) (PIC) (TLR3 agonist). Using a protection quantification paradigm, groups of mice were PIC treated and then subdivided into groups challenged with escalating doses of HSV-2. Using this paradigm, a temporal window of PIC efficacy for single applications was defined as 1 day prior to (prophylactic) through 4 h after (therapeutic) viral challenge. PIC treatment within this window protected against 10-fold-higher HSV-2 challenges, as indicated by increased 50% infectious dose values relative to those for vehicle-treated controls. Disease resolution and survival were significantly enhanced by repetitive PIC doses. Using optimal PIC regimens, cytokine induction was evaluated in murine vaginal lavages and in human vaginal epithelial cells. Similar induction patterns were observed, with kinetics that explained the limited durability of PIC-afforded protection. Daily PIC delivery courses did not generate sustained cytokine levels in murine vaginal fluids that would be indicative of local immunotoxicity. No evidence of immunotoxicity was observed in selected organs that were analyzed following repetitive vaginal PIC doses. Animal and in vitro data indicate that PIC may prove to be a valuable preventative microbicide and/or therapeutic agent against genital herpes by increasing resistance to HSV-2 and enhancing disease resolution following a failure of prevention.

Original languageEnglish (US)
Pages (from-to)9988-9997
Number of pages10
JournalJournal of Virology
Volume80
Issue number20
DOIs
StatePublished - Oct 2006

Fingerprint

Human herpesvirus 2
Herpes Genitalis
polyinosinic-polycytidylic acid
Human Herpesvirus 2
Virus Diseases
genitalia
immunotoxicity
infection
dosage
Anti-Infective Agents
agonists
mice
cytokines
Vaginal Douching
anti-infective agents
Toll-Like Receptor 9
Cytokines
Poly C
therapeutics
Oligodeoxyribonucleotides

ASJC Scopus subject areas

  • Immunology

Cite this

Quantification of poly(I : C)-mediated protection against genital herpes simplex virus type 2 infection. / Herbst-Kralovetz, Melissa M.; Pyles, Richard.

In: Journal of Virology, Vol. 80, No. 20, 10.2006, p. 9988-9997.

Research output: Contribution to journalArticle

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