Tenofovir Selectively Regulates Production of Inflammatory Cytokines and Shifts the IL-12/IL-10 Balance in Human Primary Cells

Melchjorsen, Jesper; Risør, Michael W.; Søgaard, Ole Schmeltz; O’Loughlin, Kieran L.; Chow, Sue; Paludan, Søren R.; Ellermann-Eriksen, Svend; Hedley, David W.; Minderman, Hans; Østergaard, Lars; Tolstrup, Martin

doi:10.1097/qai.0b013e3182185276

Cited by 69 publications

(71 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16 In the present study, we found that topical TFV treatment altered the vaginal cytokine-profile at 48 h after HSV-2 infection compared to controls (Fig. 4).…”

mentioning

confidence: 54%

“…[13][14][15] We have previously shown that in human primary PBMCs TDF reduced IL-10 secretion, enhanced IL-12 secretion, and decreased proinflammatory cytokine secretion in response to a bacterial or viral infection or to the stimulation of innate, pathogen-sensing, toll-like receptors. 16 In the present study, we hypothesized that an anti-HSV-2 effect of vaginally applied TFV could be verified in a vaginal challenge mouse model. The study design was similar to that used in the CAPRISA 004 study with application of TFV once before and once after virus challenge.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antiviral and Immunological Effects of Tenofovir Microbicide in Vaginal Herpes Simplex Virus 2 Infection

Vibholm

Reinert

Søgaard

et al. 2012

AIDS Research and Human Retroviruses

Self Cite

View full text Add to dashboard Cite

The anti-HIV microbicide, tenofovir (TFV) gel, has been shown to decrease HIV-1 acquisition by 39% and reduce herpes simplex virus 2 (HSV-2) transmission by 51%. We evaluated the effect of a 1% TFV gel on genital HSV-2 infection in a mouse vaginal challenge model. In vitro plaque assays and luminex multiplex bead analysis were used, respectively, to measure postinfection vaginal viral shedding (day 1) and cytokine secretion (day 2). To further investigate the anti-HSV-2 properties, we evaluated the direct antiviral effect of TFV and the oral prodrug tenofovir disoproxil fumerate (TDF) in cell culture. Compared to placebo-treated mice, TFV-treated mice had significantly lower clinical scores, developed later genital lesions, and showed reduced vaginal viral shedding. Furthermore, the levels of IFN-γ, IL-2, TNF-α, and other cytokines were altered in the vaginal fluid following topical tenofovir treatment and subsequent HSV-2 challenge. Finally, we found that both TFV and TDF inhibited HSV-2 infection in vitro; TDF showed a 50-fold greater potency than TFV. In conclusion, we confirmed that the microbicide TFV had direct anti-HSV-2 effects in a murine vaginal challenge model. Therefore, this model would be suitable for evaluating present and future microbicide candidates. Furthermore, the present study warrants further investigation of TDF in microbicides.

show abstract

“…16 In the present study, we found that topical TFV treatment altered the vaginal cytokine-profile at 48 h after HSV-2 infection compared to controls (Fig. 4).…”

mentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Antiviral and Immunological Effects of Tenofovir Microbicide in Vaginal Herpes Simplex Virus 2 Infection

Vibholm

Reinert

Søgaard

et al. 2012

AIDS Research and Human Retroviruses

Self Cite

View full text Add to dashboard Cite

show abstract

“…35 Using paired t-tests, some rectal-secretion cytokines (IL-1b, TNFa, IL-6, MIP-1a; all often classified as ''pro-inflammatory'' were shown to be reduced in the TFV-treated groups at different study stages. Given the small sample size it is of interest that when using the uncorrected cytokine results, all the subjects with reduced ex vivo infectibility at the end of the 7-day exposure period also expressed generally reduced mucosal cytokine levels (above).…”

Section: Discussionmentioning

confidence: 99%

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

Anton

Cranston

Kashuba

et al. 2012

AIDS Research and Human Retroviruses

132

176

View full text Add to dashboard Cite

This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs ( p = 0.002). Only 25% of participants liked the TFV gel. Likelihood of use ''if somewhat protective'' was *75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C max 30 min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p = 0.12, analysis of covariance (ANCOVA) p = 0.006; 7-day rectal: p = 0.02, ANCOVA p = 0.005]. Tissue PK-PD was significantly correlated ( p = 0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations.

show abstract

“…Additionally, TFV and other reverse transcriptase inhibitors (RTI) have been shown to modulate serum and cervical vaginal lavage cytokines and chemokines, as well as the response of immune cells from peripheral blood in humans and mice (19)(20)(21)(22). Overall, these results show that RTI differ in their effects on immune responses.…”

mentioning

confidence: 56%

Effects of Tenofovir on Cytokines and Nucleotidases in HIV-1 Target Cells and the Mucosal Tissue Environment in the Female Reproductive Tract

Biswas

Rodriguez-García

Shen

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Tenofovir Selectively Regulates Production of Inflammatory Cytokines and Shifts the IL-12/IL-10 Balance in Human Primary Cells

Cited by 69 publications

References 54 publications

Antiviral and Immunological Effects of Tenofovir Microbicide in Vaginal Herpes Simplex Virus 2 Infection

Antiviral and Immunological Effects of Tenofovir Microbicide in Vaginal Herpes Simplex Virus 2 Infection

RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Tenofovir 1% Gel Compared with Oral Tenofovir Disoproxil Fumarate

Effects of Tenofovir on Cytokines and Nucleotidases in HIV-1 Target Cells and the Mucosal Tissue Environment in the Female Reproductive Tract

Contact Info

Product

Resources

About