Activation by 9-(<i>R</i>)-[2-(Phosphonomethoxy)Propyl]Adenine of Chemokine (RANTES, Macrophage Inflammatory Protein 1α) and Cytokine (Tumor Necrosis Factor Alpha, Interleukin-10 [IL-10], IL-1β) Production

Zı́dek, Zdeňek; Franková, Daniela; Holý, Antonı́n

doi:10.1128/aac.45.12.3381-3386.2001

Cited by 48 publications

(36 citation statements)

References 64 publications

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“…This positive effect of acyclic nucleotide analogues may balance simultaneous activation of MCP-1 gene expression, which may have controversial pharmacological activity. A number of cytokine and beta chemokine genes influenced upon stimulation with ANPs [5,6] have been extended to MCP-1 and MCP-3 in present article. NF-jB seems to play important role in undermining expression of revealed effects.…”

Section: Discussionmentioning

confidence: 98%

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Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3

et al. 2006

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Acyclic nucleoside phosphonates are potent antiviral agents effective against replication of DNA viruses and retroviruses including human immunodeficiency virus (HIV). In addition to their antimetabolic mode of antiviral action, acyclic nucleoside phosphonates also possess immunomodulatory properties. We have shown recently that a number of them stimulate secretion of cytokines including chemokines RANTES/CCL5 ("regulated upon activation, normal T cell expressed and secreted") and MIP-1 alpha/CCL3 (macrophage inflammatory protein-1 alpha) that may inhibit entry of HIV in cells. In present experiments we analyzed effects of acyclic nucleoside phosphonates on gene expression of other members of the beta family of chemokines, monocyte chemotactic proteins (MCPs), which have also been implicated in the control of HIV infection. The following compounds differing at the type of heterocyclic base, i.e. adenine (A), or 2,6-diaminopurine (DAP), at the 6-amino group of the base, and at the N ( 9 )-side chain represented by 9-[2-(phosphonomethoxy)ethyl] (PME) and 9-[2-(phosphonomethoxy)propyl] (PMP) moieties were included in the study: (1) (R)-PMPA, ie. tenofovir, (2) N ( 6 )-cyclopropyl-(R)-PMPDAP, (3) N ( 6 )-cyclopentyl-(R)-PMPDAP, (4) N ( 6 )-dimethylaminoethyl-(R)-PMPDAP, (5) N ( 6 )-cyclopentyl-PMEDAP, (6) N ( 6 )-isobutyl-PMEDAP, (7) N ( 6 ) -cyclohexylmetyl-PMEDAP, and (8) N ( 6 ) -cyclooctyl-PMEDAP. These compounds are able to activate production of MCP-1 and MCP-3, and none of them influences gene expression of MCP-2, and MCP-5. Enhancement of monocyte chemotactic protein expression was found to be mediated by transcriptional factor nuclear factor-kappaB (NF-kappaB).

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Section: Discussionmentioning

confidence: 98%

“…They enhance production of virustatic molecule of nitric oxide and stimulate secretion of cytokines (TNFalpha), including chemokines RANTES/CCL5 and MIP-1alpha/CCL3 [5,6]. These chemokines are ligands of chemokine receptor CCR5 which is used as a coreceptor for the entry of HIV-1 in cells.…”

Section: Introductionmentioning

confidence: 99%

Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3

et al. 2006

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“…variety of chemokines and cytokines, including TNF-a and IL1b. 38 Combined with reports from MTN-007, 39 these findings merit ongoing attention in future trials. Although the participants demonstrated high adherence by the measures used, it was quite clear that only a minority of TFV gel recipients liked the product, providing an additional, user-based rationale to develop/test rectal specific formulations.…”

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

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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.

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“…Immunomodulatory effects of tenofovir and related compounds have been extensively demonstrated in murine models in vitro and in vivo, including enhancement of NK cell activity and secretion of cytokines and chemokines (13,14,94,99,100). During in vitro experiments with PBMC of uninfected rhesus macaques, tenofovir did not directly stimulate NK cell activity or cytokine production but primed cells for more rapid and enhanced interleukin-12 (IL-12) production following exposure to bacterial antigens (K. K. A.…”

Section: The Cutoff Value Was 50 Sfc Per Million Cells Prior To the mentioning

confidence: 99%

CD8⁺-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

Rompay

Singh

Pahar

et al. 2004

J Virol

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The ability of tenofovir to suppress viremia in simian immunodeficiency virus (SIV)-infected macaques for years despite the presence of virulent viral mutants with reduced in vitro susceptibility is unprecedented in this animal model. In vivo cell depletion experiments demonstrate that tenofovir's ability to suppress viremia during acute and chronic infection is significantly dependent on the presence of CD8 ؉ lymphocytes. Continuous tenofovir treatment was required to maintain low viremia. Although it is unclear whether this immunemediated suppression of viremia is linked to tenofovir's direct antiviral efficacy or is due to independent immunomodulatory effects, these studies prove the concept that antiviral immune responses can play a crucial role in suppressing viremia during anti-human immunodeficiency virus drug therapy.Although highly active antiretroviral therapy (HAART) regimens provide significant progress in the clinical management of human immunodeficiency virus (HIV) infection, their longterm use is often limited by problems such as incomplete virus suppression and drug resistance. To alleviate this problem, it is believed we need to invoke the help of the immune system to help limit virus replication and/or the virus-induced immune dysfunction.Immune responses, especially cell-mediated immune responses (CD4 ϩ -T-helper cells and CD8 ϩ T lymphocytes) are thought to play an important role in controlling virus replication and determining disease-free survival. Evidence for this comes from studies in untreated long-term nonprogressors (for a review, see reference 2). In addition, macaque data have shown conclusively that CD8 ϩ lymphocytes play an important role in limiting lentivirus replication because in vivo CD8ϩ -cell depletion of untreated macaques resulted in an increase in viremia (23,34,67).A number of dilemmas exist, however, for patients receiving HAART. HAART initiated during acute HIV infection can often preserve or increase antiviral immune responses, but episodes of transient viremia may be required to maintain these responses (54, 63). In contrast, when HAART is initiated during chronic HIV infection, HIV-specific immune responses are more difficult to restore (for a review, see reference 2).The goal of immunotherapeutic strategies is to augment these antiviral immune responses to prevent the emergence and/or the replication of drug-resistant mutants during HAART or to allow simplified regimens or periods without drug treatment. Although different approaches are investigated to stimulate antiviral immune responses (e.g., structured treatment interruptions, active immunizations, and cytokines), the results have been poor or success has been limited mainly to patients with acute infection with often transient results (2,3,25,63). Progress in this area may depend on a better understanding of the contribution of antiviral immune responses to the reduction of viremia during HAART and of the complex in vivo interactions of viral replication, drug resistance, immune responses, and drug pharmacok...

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Activation by 9-(R)-[2-(Phosphonomethoxy)Propyl]Adenine of Chemokine (RANTES, Macrophage Inflammatory Protein 1α) and Cytokine (Tumor Necrosis Factor Alpha, Interleukin-10 [IL-10], IL-1β) Production

Cited by 48 publications

References 64 publications

Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3

Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3

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

CD8⁺-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

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Activation by 9-(R)-[2-(Phosphonomethoxy)Propyl]Adenine of Chemokine (RANTES, Macrophage Inflammatory Protein 1α) and Cytokine (Tumor Necrosis Factor Alpha, Interleukin-10 [IL-10], IL-1β) Production

Cited by 48 publications

References 64 publications

Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3

Acyclic nucleoside phosphonate antivirals activate gene expression of monocyte chemotactic protein 1 and 3

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

CD8+-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment

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Product

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CD8⁺-Cell-Mediated Suppression of Virulent Simian Immunodeficiency Virus during Tenofovir Treatment