Immunostimulatory CpG treatment for genital HSV-2 infections

Herbst, Melissa M.; Pyles, Richard B.

doi:10.1093/jac/dkg481

Cited by 19 publications

(26 citation statements)

References 22 publications

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“…The term microbicide implies that the compound kills microorganisms; this is somewhat misleading, because microbicides may work in a variety of ways, including disrupting the pathogen's membrane or envelope, blocking receptor interactions essential for infection, inhibiting intra-or extracellular pathogen replication, or enhancing local, mucosal immune responses, thereby reducing susceptibility (10,22,26,30). A recent experimental microbicide strategy used CpG-containing oligonucleotides (CpG-ODN) delivered topically to the vaginal mucosa to induce a local immune response that protected against HSV-2 infection (21). CpG motifs are recognized by toll-like receptor 9 (TLR9) (25).…”

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confidence: 99%

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Quantification of Poly(I:C)-Mediated Protection against Genital Herpes Simplex Virus Type 2 Infection

Herbst-Kralovetz¹,

Pyles

2006

J Virol

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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.

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confidence: 99%

“…CpG motifs are recognized by toll-like receptor 9 (TLR9) (25). When triggered by specific pathogen-produced agonists, TLR activation initiates innate immune mechanisms that are designed to limit the replication and/or spread of pathogens (1,21).…”

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confidence: 99%

Quantification of Poly(I:C)-Mediated Protection against Genital Herpes Simplex Virus Type 2 Infection

Herbst-Kralovetz¹,

Pyles

2006

J Virol

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“…Elements conferring innate immunity, in particular type I IFNs, NK cells, IFN-␥, and IL-15, are all necessary for the early control of viral replication (1,2,5,13,18,19,32). Our previous study outlined that, without an adequate innate immune response, a protective adaptive response is not sufficient against HSV-2 infection (12).…”

Section: Discussionmentioning

confidence: 99%

“…Innate immunity is the first line of defense against pathogens, and its role in early control of HSV-2 is well established. Several groups have shown that NK cells, early gamma interferon (IFN-␥) production, and type I IFNs play critical roles in controlling early replication of HSV-2 (1,2,5,13,18,19,32). Recently we have shown that IL-15 also contributes to the innate antiviral responses against herpesvirus (14).…”

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confidence: 99%

Overexpression of Interleukin-15 Compromises CD4-Dependent Adaptive Immune Responses against Herpes Simplex Virus 2

Gill

Ashkar

2009

J Virol

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Interleukin-15 (IL-15) is necessary for the development and function of NK/NKT cells and the maintenance of naive and memory CD8؉ T cells. In the absence of IL-15, protective innate immunity is not available; however, a functional adaptive immune response against vaginal herpes simplex virus 2 (HSV-2) is generated. Mice overexpressing IL-15 (IL-15tg mice) have higher numbers of NK cells, greater NK-derived gamma interferon, and more CD8 ؉ T cells. Here we examined the consequences of IL-15 overexpression for innate and adaptive immunity against genital HSV-2. Surprisingly, IL-15tg mice immunized against HSV-2 were not protected against genital HSV-2 challenge compared to control immunized mice. IL-15tg mice had a higher frequency of NK cells in the genital mucosa than control mice. However, immunized IL-15tg mice had significantly lower numbers of HSV-2-specific CD4 ؉ T cells than B6 mice. We then confirmed that CD4 ؉ T cells, but not CD8 ؉ T cells, are essential for protection against intravaginal HSV-2 challenge. Since we observed less protection in immunized IL-15tg mice, we then examined if the adaptive immune responses generated in an environment with overexpression of IL-15 could provide protection against HSV-2 in an environment with normal levels of IL-15 expression. We adoptively transferred immunized cells from IL-15tg and B6 mice into naive RAG-1 ؊/؊ mice and found that the cells from immunized IL-15tg mice were able to provide protection in this IL-15-normal environment. Our data suggest that overexpression of IL-15 results in a reduced CD4 ؉ T cell-mediated adaptive immune response against genital HSV-2.

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“…CpG motif was described as a type of Immunostimulatory Sequence (ISS) [8], in which an unmethylated cytosine-phosphate-guanosine (CpG) motif is flanked by two 5'purines and two 3'pyrimidines [13]. Being a pathogenassociated molecular pattern (PAMP), oligodeoxynucleotides (ODN) containing CpG motifs could be recognized by the Toll-like Receptor 9 (TLR9) on certain cell types of the mammalian innate immune system [1,6].…”

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confidence: 99%

Construction of Swine-Specific CpG Motif Enriched Plasmid and the Study of Its Immunostimulatory Effects Both <i>In Vitro</i> and <i>In Vivo</i>

Guo

Yuan

et al. 2012

The Journal of Veterinary Medical Science

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AbSTRACT. A swine-specific CpG motif enriched plasmid (pUC18-CpG) was constructed in this study. Its immunostimulant property was tested in vitro via lymphocyte transformation assay using swine peripheral blood mononuclear cells (PbMCs). The recombinant plasmid showed higher Stimulation Index (SI) compared to the positive control (LPS). In a following animal experiment, pUC18-CpG was coadministered with a commercial swine FMD killed vaccine. Animals in the pUC18-CpG adjuvanted groups showed much higher antibody titers during the vaccination period.

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Immunostimulatory CpG treatment for genital HSV-2 infections

Cited by 19 publications

References 22 publications

Quantification of Poly(I:C)-Mediated Protection against Genital Herpes Simplex Virus Type 2 Infection

Quantification of Poly(I:C)-Mediated Protection against Genital Herpes Simplex Virus Type 2 Infection

Overexpression of Interleukin-15 Compromises CD4-Dependent Adaptive Immune Responses against Herpes Simplex Virus 2

Construction of Swine-Specific CpG Motif Enriched Plasmid and the Study of Its Immunostimulatory Effects Both <i>In Vitro</i> and <i>In Vivo</i>

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