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Expert Opinion on Therapeutic Targets Jun 2015The HIV-1 gp120 envelope (Env) glycoprotein mediates attachment of virus to human target cells that display requisite receptors, CD4 and co-receptor, generally CCR5.... (Review)
Review
INTRODUCTION
The HIV-1 gp120 envelope (Env) glycoprotein mediates attachment of virus to human target cells that display requisite receptors, CD4 and co-receptor, generally CCR5. Despite high-affinity interactions with host receptors and proof-of-principle by the drug maraviroc that interference with CCR5 provides therapeutic benefit, no licensed drug currently targets gp120.
AREAS COVERED
An overview of the role of gp120 in HIV-1 entry and of sites of potential gp120 vulnerability to therapeutic inhibition is presented. Viral defenses that protect these sites and turn gp120 into a moving labyrinth are discussed together with strategies for circumventing these defenses to allow therapeutic targeting of gp120 sites of vulnerability.
EXPERT OPINION
The gp120 envelope glycoprotein interacts with host proteins through multiple interfaces and has conserved structural features at these interaction sites. In spite of this, targeting gp120 for therapeutic purposes is challenging. Env mechanisms that have evolved to evade the humoral immune response also shield it from potential therapeutics. Nevertheless, substantial progress has been made in understanding HIV-1 gp120 structure and its interactions with host receptors, and in developing therapeutic leads that potently neutralize diverse HIV-1 strains. Synergies between advances in understanding, needs for therapeutics against novel viral targets and characteristics of breadth and potency for a number of gp120-targetting lead molecules bodes well for gp120 as a HIV-1 therapeutic target.
Topics: Animals; Anti-HIV Agents; Cyclohexanes; Drug Design; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Maraviroc; Molecular Targeted Therapy; Receptors, CCR5; Triazoles
PubMed: 25724219
DOI: 10.1517/14728222.2015.1010513 -
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 -
The FEBS Journal Jun 2020The chemokine CCR5 receptor is target of maraviroc, a negative allosteric modulator of CCR5 that blocks the HIV protein gp120 from associating with the receptor, thereby...
The chemokine CCR5 receptor is target of maraviroc, a negative allosteric modulator of CCR5 that blocks the HIV protein gp120 from associating with the receptor, thereby inhibiting virus cellular entry. As noted with other G-protein-coupled receptor family members, the role of the lipid environment in CCR5 signaling remains obscure and very modestly investigated. Controversial literature on the impact of cholesterol (Chol) depletion in HIV infection and CCR5 signaling, including the hypothesis that Chol depletion could inhibit HIV infection, lead us to focus on the understanding of Chol impact in the first stages of receptor activation. To address this aim, the approach chosen was to employ reconstituted model lipid systems of controlled lipid composition containing CCR5 from two distinct expression systems: Pichia pastoris and cell-free expression. The characterization of receptor/ligand interaction in terms of total binding or competition binding assays was independently performed by plasmon waveguide resonance and fluorescence anisotropy, respectively. Maraviroc, a potent receptor antagonist, was the ligand investigated. Additionally, coarse-grained molecular dynamics simulation was employed to investigate Chol impact in the receptor-conformational flexibility and dynamics. Results obtained with receptor produced by different expression systems and using different biophysical approaches clearly demonstrate a considerable impact of Chol in the binding affinity of maraviroc to the receptor and receptor-conformational dynamics. Chol considerably decreases maraviroc binding affinity to the CCR5 receptor. The mechanisms by which this effect occurs seem to involve the adoption of distinct receptor-conformational states with restrained structural dynamics and helical motions in the presence of Chol.
Topics: Cholesterol; HIV; HIV Envelope Protein gp120; HIV Infections; Humans; Ligands; Maraviroc; Receptors, CCR5; Receptors, Virus; Saccharomycetales; Surface Plasmon Resonance; Virus Internalization
PubMed: 31738467
DOI: 10.1111/febs.15145 -
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 -
European Journal of Clinical... Nov 2014Highly active antiretroviral therapy (HAART) is the only approach for human immunodeficiency virus (HIV) infection treatment at present. Although HAART is effective in... (Review)
Review
Highly active antiretroviral therapy (HAART) is the only approach for human immunodeficiency virus (HIV) infection treatment at present. Although HAART is effective in controlling the progression of infection, it is impossible to eradicate the virus from patients. The patients have to live with the virus. Alternative ways for the cure of HIV infection have been investigated. As the major co-receptor for HIV-1 infection, C-C motif chemokine receptor 5 (CCR5) is naturally an ideal target for anti-HIV research. The first CCR5 antagonist, maraviroc, has been approved for the treatment of HIV infection. Several other CCR5 antagonists are in clinical trials. CCR5 delta32 is a natural genotype, conferring resistance to CCR5 using HIV-1 strains. Gene therapy research targeting this mutant has been conducted for HIV infection treatment. A Berlin patient has been cured of HIV infection by the transplantation of stem cells from a CCR5 delta32 genotype donor. The infusion of an engineered zinc finger nuclease (ZFN)-modified autologous cluster of differentiation 4 (CD4) T cells has been proved to be a promising direction recently. In this study, the anti-HIV research targeting CCR5 is summarized, including CCR5 antagonist development, stem cell transplantation, and gene therapy.
Topics: Anti-HIV Agents; Biological Therapy; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Drug Discovery; HIV Infections; Humans; Maraviroc; Receptors, CCR5; Triazoles
PubMed: 25027072
DOI: 10.1007/s10096-014-2173-0 -
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 -
Frontiers in Microbiology 2020Infectious diseases caused by human immunodeficiency virus (HIV) and other highly pathogenic enveloped viruses, have threatened the global public health. Most antiviral... (Review)
Review
Infectious diseases caused by human immunodeficiency virus (HIV) and other highly pathogenic enveloped viruses, have threatened the global public health. Most antiviral drugs act as passive defenders to inhibit viral replication inside the cell, while a few of them function as gate keepers to combat viruses outside the cell, including fusion inhibitors, e.g., enfuvirtide, and receptor antagonists, e.g., maraviroc, as well as virus inactivators (including attachment inhibitors). Different from fusion inhibitors and receptor antagonists that must act in the presence of target cells, virus inactivators can actively inactivate cell-free virions in the blood, through interaction with one or more sites in the envelope glycoproteins (Envs) on virions. Notably, a number of protein- and peptide-based virus inactivators (PPVIs) under development are expected to have a better utilization rate than the current antiviral drugs and be safer for human application than the chemical-based virus inactivators. Here we have highlighted recent progress in developing PPVIs against several important enveloped viruses, including HIV, influenza virus, Zika virus (ZIKV), dengue virus (DENV), and herpes simplex virus (HSV), and the potential use of PPVIs for urgent treatment of infection by newly emerging or re-emerging viruses.
PubMed: 32523582
DOI: 10.3389/fmicb.2020.01063 -
PloS One 2020Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used...
HIV antiretroviral drugs, dolutegravir, maraviroc and ritonavir-boosted atazanavir use different pathways to affect inflammation, senescence and insulin sensitivity in human coronary endothelial cells.
OBJECTIVES
Aging HIV-infected antiretroviral-treatment (ART)-controlled patients often present cardiovascular and metabolic comorbidities. Thus, it is mandatory that life-long used ART has no cardiometabolic toxicity. Protease inhibitors have been associated with cardiometabolic risk, integrase-strand-transfer-inhibitors (INSTI) with weight gain and the CCR5 inhibitor maraviroc with improved vascular function. We have previously reported that the INSTI dolutegravir and maraviroc improved, and ritonavir-boosted atazanavir(atazanavir/r) worsened, inflammation and senescence in human coronary artery endothelial cells (HCAEC)s from adult controls. Here, we analyzed the pathways involved in the drugs' effects on inflammation, senescence and also insulin resistance.
METHODS
We analyzed the involvement of the anti-inflammatory SIRT-1 pathway in HCAECs. Then, we performed a transcriptomic analysis of the effect of dolutegravir, maraviroc and atazanavir/r and used siRNA-silencing to address ubiquitin-specific-peptidase-18 (USP18) involvement into ART effects.
RESULTS
Dolutegravir reduced inflammation by decreasing NFκB activation and IL-6/IL-8/sICAM-1/sVCAM-1 secretion, as did maraviroc with a milder effect. However, when SIRT-1 was inhibited by splitomicin, the drugs anti-inflammatory effects were maintained, indicating that they were SIRT-1-independant. From the transcriptomic analysis we selected USP18, previously shown to decrease inflammation and insulin-resistance. USP18-silencing enhanced basal inflammation and senescence. Maraviroc still inhibited NFκB activation, cytokine/adhesion molecules secretion and senescence but the effects of dolutegravir and atazanavir/r were lost, suggesting that they involved USP18. Otherwise, in HCAECs, dolutegravir improved and atazanavir/r worsened insulin resistance while maraviroc had no effect. In USP18-silenced cells, basal insulin resistance was increased, but dolutegravir and atazanavir/r kept their effect on insulin sensitivity, indicating that USP18 was dispensable.
CONCLUSION
USP18 reduced basal inflammation, senescence and insulin resistance in coronary endothelial cells. Dolutegravir and atazanavir/r, but not maraviroc, exerted opposite effects on inflammation and senescence that involved USP18. Otherwise, dolutegravir improved and atazanavir/r worsened insulin resistance independently of USP18. Thus, in endothelial cells, dolutegravir and atazanavir/r oppositely affected pathways leading to inflammation, senescence and insulin resistance.
Topics: Anti-HIV Agents; Atazanavir Sulfate; Cells, Cultured; Comorbidity; Coronary Vessels; Endothelial Cells; Female; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Insulin Resistance; Male; Maraviroc; NF-kappa B; Oxazines; Piperazines; Pyridones; Ritonavir; Signal Transduction; Sirtuin 1; Ubiquitin Thiolesterase
PubMed: 31971958
DOI: 10.1371/journal.pone.0226924 -
Expert Review of Neurotherapeutics Jun 2019: The importance of excessive cerebral tumor necrosis factor (TNF) concentrations as one of the central tenets of the pathogenesis of the neurodegenerative diseases is... (Review)
Review
: The importance of excessive cerebral tumor necrosis factor (TNF) concentrations as one of the central tenets of the pathogenesis of the neurodegenerative diseases is now widely known, but variably accepted. : Here we update the field by including material that is freely available on the large databases, particularly PubMed. We include the therapeutic outcomes with etanercept (a widely used specific anti-TNF biological), XPro1595 (a new double negative TNF inhibitor), 3,6-dithiothalidomide, implanted SB623 stem cells, maraviroc (a CCR5 inhibitor used to treat AIDS), MCC950 (an NLRP3 inhibitor), and changes in the hormone irisin. : Remarkably, considering the ample literature that links SB623 cells, maraviroc, MCC950 and irisin to TNF, these publications do not mention this cytokine, and therefore not their implicit involvement with controlling its cerebral levels. With regard to developments demonstrated by MCC950, we note that DAMPs and PAMPs recognize and activate both TLRs and inflammasomes in these disease states. Here, as in other illnesses, data suggests that preventing a pathogenic interaction could be achieved through shutting down either of these arms of innate immunity.
Topics: Animals; Fibronectins; Furans; Heterocyclic Compounds, 4 or More Rings; Humans; Indenes; Maraviroc; Neurodegenerative Diseases; Stem Cell Transplantation; Sulfonamides; Sulfones; Tumor Necrosis Factor-alpha
PubMed: 31092047
DOI: 10.1080/14737175.2019.1618710 -
Experimental Neurology Apr 2021CCR5 and CXCR4 are structurally related chemokine receptors that belong to the superfamily of G-protein coupled receptors through which the HIV virus enters and infects...
CCR5 and CXCR4 are structurally related chemokine receptors that belong to the superfamily of G-protein coupled receptors through which the HIV virus enters and infects cells. Both receptors are also related to HIV-associated neurocognitive disorders that include difficulties in concentration and memory, impaired executive functions, psychomotor slowing, depression and irritability, which are also hallmarks of the long-term sequelae of TBI. Moreover, A growing body of evidence attributes negative influences to CCR5 activation on cognition, particularly after stroke and traumatic brain injury (TBI). Here we investigated the effect of their blockage on motor and cognitive functions, on brain tissue loss and preservation and on some of the biochemical pathways involved. We examined the effect of maraviroc, a CCR5 antagonist used in HIV patients as a viral entry inhibitor, and of plerixafor (AMD3100), a CXCR4 antagonist used in cancer patients as an immune-modulator, on mice subjected to closed head injury (CHI). Mice were treated with maraviroc or plerixafor after CHI for the following 4 or 5 days, respectively. Neurobehavior was assessed according to the Neurological Severity Score; cognitive tests were performed by using the Y-maze, Barnes maze and the novel object recognition test; anxiety was evaluated with the open field test. The mice were sacrificed and brain tissues were collected for Western blot, pathological and immunohistochemical analyses. Both drugs enhanced tissue preservation in the cortex, hippocampus, periventricular areas, corpus callosum and striatum, and reduced astrogliosis)GFAP expression). They also increased the levels of synaptic cognition-related signaling molecules such as phosphorylated NR1 and CREB, and the synaptic plasticity protein PSD95. Both treatments also enhanced the expression of CCR5 and CXCR4 on different brain cell types. In summary, the beneficial effects of blocking CCR5 and CXCR4 after CHI suggest that the drugs used in this study, both FDA approved and in clinical use, should be considered for translational research in TBI patients.
Topics: Animals; Benzylamines; Brain; Brain Injuries, Traumatic; CCR5 Receptor Antagonists; Cyclams; Maraviroc; Mice; Neuroprotective Agents; Receptors, CCR5; Receptors, CXCR4; Recovery of Function
PubMed: 33453212
DOI: 10.1016/j.expneurol.2021.113604