Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses

Trifonova, Radiana; Doncel, Gustavo F.; Fichorova, Raina N.

doi:10.1128/aac.01152-08

Cited by 38 publications

(34 citation statements)

References 70 publications

(73 reference statements)

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“…A recent report suggests that certain polyanionic compounds belonging to this group can interfere with TLR ligand-triggered innate immune responses by epithelial cells derived from the human female genital tract (48). Polyanionic microbicide-mediated suppression of the activities of multiple TLRs that recognize viral or bacterial components was observed (48).…”

Section: Discussionmentioning

confidence: 99%

“…Some polyanionic microbicides have been shown to inhibit the activation of multiple TLRs (TLR1, TLR2, TLR3, and TLR6) that recognize viral or bacterial components, and this inhibits innate immune responses by epithelial cells derived from the human female genital tract (48). Additionally, vaginal microflora abnormalities have been documented in clinical studies that evaluated the safety of the same class of polyanionic microbicide candidates (6,43).…”

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confidence: 99%

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Phosphorothioate 2′ Deoxyribose Oligomers as Microbicides That Inhibit Human Immunodeficiency Virus Type 1 (HIV-1) Infection and Block Toll-Like Receptor 7 (TLR7) and TLR9 Triggering by HIV-1

Fraietta

Mueller

et al. 2010

Antimicrob Agents Chemother

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Topical microbicides may prove to be an important strategy for preventing human immunodeficiency virus type 1 (HIV-1) transmission. We examined the safety and efficacy of sequence-nonspecific phosphorothioate 2 deoxyribose oligomers as potential novel microbicides. A short, 13-mer poly(T) phosphorothioate oligodeoxynucleotide (OPB-T) significantly inhibited infection of primary peripheral blood mononuclear cells (PBMC) by high-titer HIV-1 Ba-L and simian immunodeficiency virus mac251 (SIV mac251 ). Continuous exposure of human vaginal and foreskin tissue explants to OPB-T showed no toxicity. An abasic 14-mer phosphorothioate 2 deoxyribose backbone (PDB) demonstrated enhanced anti-HIV-1 activity relative to OPB-T and other homo-oligodeoxynucleotide analogs. When PDB was used to pretreat HIV-1, PDB was effective against R5 and X4 isolates at a half-maximal inhibitory concentration (IC 50 ) of <1 M in both PBMC and P4-R5 MAGI cell infections. PDB also reduced HIV-1 infectivity following the binding of virus to target cells. This novel topical microbicide candidate exhibited an excellent in vitro safety profile in human PBMC and endocervical epithelial cells. PDB also retained activity in hydroxyethylcellulose gel at pH 4.4 and after transition to a neutral pH and was stable in this formulation for 30 days at room temperature. Furthermore, the compound displayed potent antiviral activity following incubation with a Lactobacillus strain derived from normal vaginal flora. Most importantly, PDB can inhibit HIV-1-induced alpha interferon production. Phosphorothioate 2 deoxyribose oligomers may therefore be promising microbicide candidates that inhibit HIV-1 infection and also dampen the inflammation which is critical for the initial spread of the virus.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Phosphorothioate 2′ Deoxyribose Oligomers as Microbicides That Inhibit Human Immunodeficiency Virus Type 1 (HIV-1) Infection and Block Toll-Like Receptor 7 (TLR7) and TLR9 Triggering by HIV-1

Fraietta

Mueller

et al. 2010

Antimicrob Agents Chemother

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“…The End1/E6E7 cells have been validated as a model for vaginal epithelial immune function by comparisons with primary cell cultures, tissues, animal models, and clinical findings and show similar toll-like receptor and cytokine profiles to primary cells (11,47,48). End1/E6E7 cells were grown in 175-cm 2 culture flasks (Greiner Bio-One International) in keratinocyte serum-free medium (Sigma-Aldrich) supplemented with CaCl 2 (final concentration, 0.4 mM), 100 IU/ml penicillin, 100 g/ml streptomycin, the provided bovine pituitary extract, and 0.1 ng/ml recombinant EGF.…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoid-independent Repression of Tumor Necrosis Factor (TNF) α-stimulated Interleukin (IL)-6 Expression by the Glucocorticoid Receptor

Verhoog

Toit

Avenant

et al. 2011

Journal of Biological Chemistry

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TNF␣ signaling and cytokine levels play a crucial role in cervical immunity and the host response to infections. We investigated the role of liganded and unliganded glucocorticoid receptor (GR) in IL-6 and IL-8 gene regulation in response to TNF␣ in the End1/E6E7 immortalized human endocervical epithelial cell line. In the absence of glucocorticoids, both decreasing GR protein levels by an siRNA strategy and results with the GR antagonist RU486 suggest a role for the unliganded GR in reduction of TNF␣-induced IL-6 and IL-8 mRNA levels in End1/E6E7 cells. Moreover, GR-dependent repression of endogenous IL-6 mRNA as well as a minimal IL-6 promoter-reporter gene is also demonstrated in COS-1 cells in the absence of GR ligand, suggesting a transcriptional mechanism that is not cell-specific. TNF␣ induced recruitment of both the unliganded GR and GRinteracting protein type 1 (GRIP-1) to the IL-6 promoter. This, together with GRIP-1 overexpression studies, suggests a function for GRIP-1 as a GR co-repressor in this context. TNF␣ was shown to induce phosphorylation of the unliganded human GR at Ser-226 but not Ser-211, unlike dexamethasone, which induced hyperphosphorylation at both serine residues. Ser-226 is shown to be required for the ligand-independent GR-mediated repression of IL-6 in response to TNF␣. Taken together, these results support a model whereby the unliganded GR attenuates TNF␣-stimulated IL-6 transcription by a mechanism involving selective phosphorylation and recruitment of the unliganded GR and GRIP-1 to the IL-6 promoter. These findings suggest the presence of a novel autoregulatory mechanism that may prevent overproduction of IL-6 in the endocervix, possibly protecting against negative effects of excessive inflammation.

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“…It has been demonstrated that other similar polyanions interfere with epithelial secretion of cervicovaginal innate and inflammatory factors. 42 The polyanionic microbicide compounds dextran sulfate and polystyrene sulfonate significantly inhibited cytokine mRNA and protein levels of proinflammatory (IL-8 and IL-1beta) and antiviral (beta interferon) cytokines following epithelial cell stimulation with TLR ligands Pam(3)CSK(4), MALP-2, or poly(I:C). These activities were associated with the sulfate/sulfonate moieties of the polyanionic compounds, since the unsulfated dextran control did not show any effects.…”

Section: Vaginal Safety Of Cs Hec Placebo and N-9mentioning

confidence: 99%

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Mauck

Lai

Weiner

et al. 2013

AIDS Research and Human Retroviruses

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TitleToward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure. Several microbicides, including nonoxynol-9 (N-9) and cellulose sulfate (CS), looked promising during early trials but failed in efficacy trials. We aimed to identify Phase I mucosal safety endpoints that might explain that failure. In a blinded, randomized, parallel trial, 60 healthy premenopausal sexually abstinent women applied Universal HEC placebo, 6% CS or 4% N-9 gel twice daily for 13½ days. Endpoints included immune biomarkers in cervicovaginal lavage (CVL) and endocervical cytobrushes, inflammatory infiltrates in vaginal biopsies, epithelial integrity by naked eye, colposcopy, and histology, CVL anti-HIV activity, vaginal microflora, pH, and adverse events. Twenty women enrolled per group. Soluble/cellular markers were similar with CS and placebo, except secretory leukocyte protease inhibitor (SLPI) levels decreased in CVL, and CD3 + and CD45 + cells increased in biopsies after CS use. Increases in interleukin (IL)-8, IL-1, IL-1RA, and myeloperoxidase (MPO) and decreases in SLPI were significant with N-9. CVL anti-HIV activity was significantly higher during CS use compared to N-9 or placebo. CS users tended to have a higher prevalence of intermediate Nugent score, Escherichia coli, and Enterococcus and fewer gram-negative rods. Most Nugent scores diagnostic for bacterial vaginosis were in N-9 users. All cases of histological inflammation or deep epithelial disruption occurred in N-9 users. While the surfactant N-9 showed obvious biochemical and histological signs of inflammation, more subtle changes, including depression of SLPI, tissue influx of CD45 + and CD3 + cells, and subclinical microflora shifts were associated with CS use and may help to explain the clinical failure of nonsurfactant microbicides.

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Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses

Cited by 38 publications

References 70 publications

Phosphorothioate 2′ Deoxyribose Oligomers as Microbicides That Inhibit Human Immunodeficiency Virus Type 1 (HIV-1) Infection and Block Toll-Like Receptor 7 (TLR7) and TLR9 Triggering by HIV-1

Phosphorothioate 2′ Deoxyribose Oligomers as Microbicides That Inhibit Human Immunodeficiency Virus Type 1 (HIV-1) Infection and Block Toll-Like Receptor 7 (TLR7) and TLR9 Triggering by HIV-1

Glucocorticoid-independent Repression of Tumor Necrosis Factor (TNF) α-stimulated Interleukin (IL)-6 Expression by the Glucocorticoid Receptor

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

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