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Frontiers in Immunology 2022
Topics: HIV-1; Receptors, CCR5
PubMed: 36330512
DOI: 10.3389/fimmu.2022.1054430 -
Haematologica Mar 2019Classic Hodgkin lymphoma tumor cells express a functional CCR5 receptor, and tumor tissues express high CCL5 levels, suggesting that CCL5-CCR5 signaling is involved in...
Classic Hodgkin lymphoma tumor cells express a functional CCR5 receptor, and tumor tissues express high CCL5 levels, suggesting that CCL5-CCR5 signaling is involved in tumor-microenvironment formation and tumor growth. Using the CCR5 antagonist, maraviroc, and a neutralizing anti-CCL5 antibody, we found that CCL5 secreted by classic Hodgkin lymphoma cells recruited mesenchymal stromal cells and monocytes. The "education" of mesenchymal stromal cells by tumor cell-conditioned medium enhanced mesenchymal stromal cells' proliferation and CCL5 secretion. In turn, educated mesenchymal stromal cell-conditioned medium increased the clonogenic growth of tumor cells and monocyte migration, but these effects were reduced by maraviroc. Monocyte education by tumor cell-conditioned medium induced their growth and reprogrammed them towards immunosuppressive tumor-associated macrophages that expressed IDO and PD-L1 and secreted IL-10, CCL17 and TGF-β. Educated monocyte-conditioned medium slowed the growth of phytohemagglutinin-activated lymphocytes. Maraviroc decreased tumor cell growth and synergized with doxorubicin and brentuximab vedotin. A three-dimensional heterospheroid assay showed that maraviroc counteracted both the formation and viability of heterospheroids generated by co-cultivation of tumor cells with mesenchymal stromal cells and monocytes. In mice bearing tumor cell xenografts, maraviroc reduced tumor growth by more than 50% and inhibited monocyte accumulation, without weight loss. Finally, in classic Hodgkin lymphoma human tumor tissues, CCL5 and CD68 expression correlated positively, and patients with high CCL5 levels had poor prognosis. In conclusion, since the present challenges are to find molecules counteracting the formation of the immunosuppressive tumor microenvironment or new, less toxic drug combinations, the repurposed drug maraviroc may represent a new opportunity for classic Hodgkin lym phoma treatment.
Topics: Animals; CCR5 Receptor Antagonists; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cells, Cultured; Cellular Reprogramming; Disease Models, Animal; Doxorubicin; Drug Synergism; Hodgkin Disease; Humans; Maraviroc; Mice; Models, Biological; Monocytes; Receptors, CCR5; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 30309853
DOI: 10.3324/haematol.2018.196725 -
PloS One 2013Immunological non-responders (INRs) lacked CD4 increase despite HIV-viremia suppression on HAART and had an increased risk of disease progression. We assessed immune... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Immunological non-responders (INRs) lacked CD4 increase despite HIV-viremia suppression on HAART and had an increased risk of disease progression. We assessed immune reconstitution profile upon intensification with maraviroc in INRs.
METHODS
We designed a multi-centric, randomized, parallel, open label, phase 4 superiority trial. We enrolled 97 patients on HAART with CD4+<200/µL and/or CD4+ recovery ≤ 25% and HIV-RNA<50 cp/mL. Patients were randomized 1:1 to HAART+maraviroc or continued HAART. CD4+ and CD8+ CD45+RA/RO, Ki67 expression and plasma IL-7 were quantified at W0, W12 and W48.
RESULTS
By W48 both groups displayed a CD4 increase without a significant inter-group difference. A statistically significant change in CD8 favored patients in arm HAART+maraviroc versus HAART at W12 (p=.009) and W48 (p=.025). The CD4>200/µL and CD4>200/µL + CD4 gain ≥ 25% end-points were not satisfied at W12 (p=.24 and p=.619) nor at W48 (p=.076 and p=.236). Patients continuing HAART displayed no major changes in parameters of T-cell homeostasis and activation. Maraviroc-receiving patients experienced a significant rise in circulating IL-7 by W48 (p=.01), and a trend in temporary reduction in activated HLA-DR+CD38+CD4+ by W12 (p=.06) that was not maintained at W48.
CONCLUSIONS
Maraviroc intensification in INRs did not have a significant advantage in reconstituting CD4 T-cell pool, but did substantially expand CD8. It resulted in a low rate of treatment discontinuations.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00884858 http://clinicaltrials.gov/show/NCT00884858.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biomarkers; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclohexanes; Female; HIV Infections; HIV-1; Humans; Immunocompromised Host; Interleukin-7; Ki-67 Antigen; Male; Maraviroc; Middle Aged; RNA, Viral; Treatment Outcome; Triazoles; Viral Load
PubMed: 24244635
DOI: 10.1371/journal.pone.0080157 -
Journal of Biomolecular Structure &... Aug 2021Non-Structural Protein 16 (nsp-16), a viral RNA methyltransferase (MTase), is one of the highly viable targets for drug discovery of coronaviruses including SARS-CoV-2....
Non-Structural Protein 16 (nsp-16), a viral RNA methyltransferase (MTase), is one of the highly viable targets for drug discovery of coronaviruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been performed by a virtual drug repurposing approach. First, drug shape-based screening (among FDA approved drugs) with a known template of MTase inhibitor, sinefungin was done and best compounds with high similarity scores were selected. In addition to the selected compounds, 4 nucleoside analogs of anti-viral (Raltgravir, Maraviroc and Favipiravir) and anti-inflammatory (Prednisolone) drugs were selected for further investigations. Then, binding energies and interaction modes were found by molecular docking approaches and compouds with lower energy were selected for further investigation. After that, Molecular dynamics (MD) simulation was carried to test the potential selected compounds in a realistic environment. The results showed that Raltegravir and Maraviroc among other compounds can bind strongly to the active site of the protein compared to sinefungin, and can be potential candidates to inhibit NSP-16. Also, the MD simulation results suggested that the Maraviroc and Raltegravir are more effective drug candidates than Sinefungin for inhibiting the enzyme. It is concluded that Raltegravir and Maraviroc which may be used in the treatment of COVID-19 after Invitro and invivo studies and clinical trial for final confirmation of drug effectiveness. Communicated by Ramaswamy H. Sarma.
Topics: Antiviral Agents; COVID-19; Drug Repositioning; Humans; Molecular Docking Simulation; SARS-CoV-2
PubMed: 32573355
DOI: 10.1080/07391102.2020.1779133 -
PloS One 2023Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further exploration.
METHODS
We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores.
RESULTS
Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6-7.8) kPa, 325 (IQR 279-351) dB/m and 9.1 (IQR 8.6-9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores.
CONCLUSIONS
This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis.
TRIAL REGISTRATION
Clinical trial registry: ISCRTN, registration number 31461655.
Topics: Humans; Male; Female; Non-alcoholic Fatty Liver Disease; Maraviroc; Diabetes Mellitus, Type 2; Feasibility Studies; Liver Cirrhosis; HIV Infections; Elasticity Imaging Techniques; HIV-1; Liver
PubMed: 37450478
DOI: 10.1371/journal.pone.0288598 -
European Stroke Journal Sep 2022Current evidence suggest that 25%-33% of stroke-survivors develop post-stroke cognitive impairment (PSCI). The licensed drug Maraviroc, a CCR5-antagonist, is postulated...
Preventing post-stroke dementia. The MARCH Trial. Protocol and statistical analysis plan of a randomized clinical trial testing the safety and efficacy of Maraviroc in post-stroke cognitive impairment.
BACKGROUND
Current evidence suggest that 25%-33% of stroke-survivors develop post-stroke cognitive impairment (PSCI). The licensed drug Maraviroc, a CCR5-antagonist, is postulated to act via a neuroprotective mechanism that may offer the potential of preventing progression to vascular dementia. Our hypothesis: Maraviroc may have the potential to augment learning skills and cognitive performance by affecting synaptic plasticity, along with neuro-inflammatory modulation in patients with cerebral small vessel disease (SVD) and PSCI.
DESIGN
MARCH is a multi-center, double-blind randomized-control Phase-II trial of Maraviroc 150 or 600 mg/day versus placebo for 12-months in five stroke centers in Israel. Included are patients diagnosed with recent (1-24 months) subcortical stroke who experience mild PSCI and have evidence of white matter lesions and SVD on neuroimaging.
OUTCOMES
Primary outcomes: 1. Change in cognitive scores. 2. Drug related adverse events. Secondary outcomes: change in functional and affective scores, MRI-derived measures, inflammatory markers, carotid atherosclerosis, cerebrospinal-fluid biomarkers in a sub-study. A sample size of 60 in each treatment group and 30 in the placebo group (total - 150 participants) provides 80% power between the treatment and the placebo groups.
CONCLUSIONS
The results of this work could lead to a novel, readily available, therapeutic avenue to reduce PSCI, and possibly other pathologies. This study will test safety and effectiveness of Maraviroc in limiting cognitive deterioration and/or post stroke cognitive impairment in patients with cerebral small vessel disease.
SCHEDULE
First-patient first-visit was May 2021. Recruitment to complete in 2023, follow-up to complete in 2024.
PubMed: 36082248
DOI: 10.1177/23969873221098857 -
British Journal of Clinical Pharmacology Apr 2008To assess the effect of a single dose of maraviroc on the QTc interval in healthy subjects and to evaluate the QTc interval-concentration relationship. (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
To assess the effect of a single dose of maraviroc on the QTc interval in healthy subjects and to evaluate the QTc interval-concentration relationship.
METHODS
A single-dose, placebo- and active-controlled, five-way crossover study was conducted to investigate the effects of maraviroc (100, 300, 900 mg) on QTc in healthy subjects. Moxifloxacin (400 mg) was used as the active comparator. The study was double-blind with respect to maraviroc/placebo and open label for moxifloxacin. There was a 7-day wash-out period between each dose. QT interval measurements obtained directly from the electrocardiogram (ECG) recorder were corrected for heart rate using Fridericia's correction (QTcF). A placebo run-in day was conducted before period 3, when ECGs were collected at intervals while subjects were resting or during exercise. These ECGs plus other predose ECGs were used to evaluate the QT/RR relationship for each subject to enable calculation of an individual's heart rate correction for their QT measurements (QTcI). ECGs were taken at various intervals pre- and postdose in each study period. Pharmacokinetic parameters were determined for each maraviroc dose. The end-points that were evaluated were QTcF at median time to maximum concentration (T(max)) based on the machine readings and QTcI at median T(max) based on manual over-reads of the QT/RR data. A separate analysis of variance was used for each of the pair-wise comparisons for each end-point. The relationship between QTc interval and plasma concentration was also investigated using a mixed-effects modelling approach, as implemented by the NONMEM software system. A one-stage model was employed in which the relationship between QT and RR and the effects of maraviroc plasma concentration on QT were estimated simultaneously.
RESULTS
The mean difference from placebo in machine-read QTcF at median T(max) for maraviroc 900 mg was 3.6 ms [90% confidence interval (CI) 1.5, 5.8]. For the active comparator, moxifloxacin, the mean difference from placebo in machine-read QTcF was 13.7 ms. The changes from placebo for each of the end-points were similar for men and women. No subjects receiving maraviroc or placebo had a QTcF > or = 450 ms (men) or QTcF > or = 470 ms (women), nor did any subject experience a QTcF increase > or = 60 ms from baseline at any time point. Analysis based on the QTcI data obtained from the manual over-readings of the ECGs gave numerically very similar results. The QT:RR relationship was similar pre- and postdose and was not related to maraviroc concentration. The population estimate of the QT:RR correction factor was 0.324 (95% CI 0.309, 0.338). The population estimate of the slope describing the QT-concentration relationship was 0.97 micros ml ng(-1) (95% CI -0.571, 2.48), equivalent to an increase of 0.97 ms in QT per 1000 ng maraviroc plasma concentration. Most adverse events were mild to moderate in severity.
CONCLUSIONS
Single doses of maraviroc, up to and including 900 mg, had no clinically relevant effect on QTcF or QTcI. At all maraviroc doses and for both end-points, the mean difference from placebo for QTc was < 4 ms. There was no apparent relationship between QT interval and maraviroc plasma concentration up to 2363 ng ml(-1). This conclusion held in both male and female subjects, and there was no evidence of a change in the QT/RR relationship with concentration.
Topics: Adolescent; Adult; Anti-Infective Agents; Aza Compounds; CCR5 Receptor Antagonists; Cyclohexanes; Electrocardiography; Epidemiologic Methods; Female; Fluoroquinolones; Heart Rate; Humans; Male; Maraviroc; Middle Aged; Models, Biological; Moxifloxacin; Quinolines; Triazoles
PubMed: 18333868
DOI: 10.1111/j.1365-2125.2008.03138.x -
Biochemical Society Transactions Jun 2021The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine... (Review)
Review
The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine system has been linked to inflammatory diseases and cancer, which renders chemokine receptors to be considered as therapeutic targets. In the past two decades, around 45 drugs targeting chemokine receptors have been developed, yet only three are clinically approved. The challenging factors include the limited understanding of aberrant chemokine signalling in malignant diseases, high redundancy of the chemokine system, differences between cell types and non-specific binding of the chemokine receptor antagonists due to the broad ligand-binding pockets. In recent years, emerging studies attempt to characterise the chemokine ligand-receptor interactions and the downstream signalling protein-protein interactions, aiming to fine tuning to the promiscuous interplay of the chemokine system for the development of precision medicine. This review will outline the updates on the mechanistic insights in the chemokine system and propose some potential strategies in the future development of targeted therapy.
Topics: Animals; Antibodies, Monoclonal, Humanized; Benzylamines; Chemokines; Cyclams; Humans; Inflammation; Maraviroc; Molecular Targeted Therapy; Neoplasms; Protein Binding; Receptors, Chemokine; Signal Transduction
PubMed: 34060588
DOI: 10.1042/BST20201114 -
Gels (Basel, Switzerland) Dec 2021The challenges encountered with conventional microbicide gels has necessitated the quest for alternative options. This study aimed to formulate and evaluate a bigel and...
Enzyme Responsive Vaginal Microbicide Gels Containing Maraviroc and Tenofovir Microspheres Designed for Acid Phosphatase-Triggered Release for Pre-Exposure Prophylaxis of HIV-1: A Comparative Analysis of a Bigel and Thermosensitive Gel.
The challenges encountered with conventional microbicide gels has necessitated the quest for alternative options. This study aimed to formulate and evaluate a bigel and thermosensitive gel, designed to combat the challenges of leakage and short-residence time in the vagina. Ionic-gelation technique was used to formulate maraviroc and tenofovir microspheres. The microspheres were incorporated into a thermosensitive gel and bigel, then evaluated. Enzyme degradation assay was used to assess the effect of the acid phosphatase enzyme on the release profile of maraviroc and tenofovir microspheres. HIV efficacy and cytotoxicity of the microspheres were assessed using HIV-1-BaL virus strain and HeLa cell lines, respectively. Maraviroc and tenofovir release kinetics followed zero-order and Higuchi model kinetics. However, under the influence of the enzyme, maraviroc release was governed by first-order model, while tenofovir followed a super case II transport-mechanism. The altered mode of release and drug transport mechanism suggests a triggered release. The assay of the microspheres suspension on the HeLa cells did not show signs of cytotoxicity. The thermosensitive gel and bigel elicited a progressive decline in HIV infectivity, until at concentrations of 1 μg/mL and 0.1 μg/mL, respectively. The candidate vaginal gels have the potential for a triggered release by the acid phosphatase enzyme present in the seminal fluid, thus, serving as a strategic point to prevent HIV transmission.
PubMed: 35049550
DOI: 10.3390/gels8010015 -
Current Opinion in HIV and AIDS Nov 2012Clinical trials of oral preexposure prophylaxis (PrEP) have focused on regimens of tenofovir (TDF) with or without emtricitabine (FTC). However, TDF may be associated... (Review)
Review
PURPOSE OF REVIEW
Clinical trials of oral preexposure prophylaxis (PrEP) have focused on regimens of tenofovir (TDF) with or without emtricitabine (FTC). However, TDF may be associated with toxicities (renal, bone), and FTC may select for drug resistance. Both are also first-line drugs for HIV treatment. In this review, we discuss agents that might serve as alternatives to TDF/FTC for HIV PrEP.
RECENT FINDINGS
Several drug characteristics are important to consider when selecting agents for PrEP with the most critical being safety, tolerability, adequate penetration into target tissues for prevention of HIV infection, and long-lasting activity with convenient dosing. With these factors in mind, we review five potentially useful agents for PrEP. The first group includes drugs that are already Food and Drug Administration approved (maraviroc, raltegravir) with attributes that make them attractive for PrEP. The second group includes investigational agents with long-lasting activity that are being developed in parenteral form (rilpivirine-long acting, S/GSK1265744, ibalizumab).
SUMMARY
Future PrEP drugs may give clinicians the flexibility to select agents on the basis of individual patient needs and preferences.
Topics: Administration, Oral; Anti-HIV Agents; Chemoprevention; HIV Infections; Humans
PubMed: 23032733
DOI: 10.1097/COH.0b013e328358b9ce