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Autophagy Apr 2024In the prodromal phase of neurodegenerative diseases, microglia switch to an activated state resulting in increased secretion of pro-inflammatory factors. We reported...
In the prodromal phase of neurodegenerative diseases, microglia switch to an activated state resulting in increased secretion of pro-inflammatory factors. We reported that C - C chemokine ligand 3 (CCL3), C - C chemokine ligand 4 (CCL4) and C - C chemokine ligand 5 (CCL5) contained in the secretome of activated microglia inhibit neuronal autophagy via a non-cell autonomous mechanism. These chemokines bind and activate neuronal C - C chemokine receptor type 5 (CCR5), which, in turn, promotes phosphoinositide 3-kinase (PI3K) - protein kinase B (PKB, or AKT) - mammalian target of rapamycin complex 1 (mTORC1) pathway activation, which inhibits autophagy, thus causing the accumulation of aggregate-prone proteins in the cytoplasm of neurons. The levels of CCR5 and its chemokine ligands are increased in the brains of pre-manifesting Huntington disease (HD) and tauopathy mouse models. CCR5 accumulation might be due to a self-amplifying mechanism, since CCR5 is a substrate of autophagy and CCL5-CCR5-mediated autophagy inhibition impairs CCR5 degradation. Furthermore, pharmacological, or genetic inhibition of CCR5 rescues mTORC1-autophagy dysfunction and improves neurodegeneration in HD and tauopathy mouse models, suggesting that CCR5 hyperactivation is a pathogenic signal driving the progression of these diseases.
Topics: Animals; Humans; Mice; Autophagy; Cytokines; Mechanistic Target of Rapamycin Complex 1; Microglia; Molecular Targeted Therapy; Neurons; Receptors, CCR5; Signal Transduction
PubMed: 37358357
DOI: 10.1080/15548627.2023.2221921 -
Nature Reviews. Neurology Feb 2016Chemokine receptors have been implicated in a wide range of CNS inflammatory diseases and have important roles in the recruitment and positioning of immune cells within... (Review)
Review
Chemokine receptors have been implicated in a wide range of CNS inflammatory diseases and have important roles in the recruitment and positioning of immune cells within tissues. Among them, the chemokine (C-C motif) receptor 5 (CCR5) can be targeted by maraviroc, a readily available and well-tolerated drug that was developed for the treatment of HIV. Correlative evidence implicates the CCR5-chemokine axis in multiple sclerosis, Rasmussen encephalitis, progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome, and infectious diseases, such as cerebral malaria and HIV-associated neurocognitive disorders. On the basis of this evidence, we postulate in this Review that CCR5 antagonists, such as maraviroc, offer neuroprotective benefits in settings in which CCR5 promotes deleterious neuroinflammation, particularly in diseases in which CD8(+) T cells seem to play a pivotal role.
Topics: Animals; CCR5 Receptor Antagonists; Central Nervous System Diseases; HIV Infections; Humans; Neuroimmunomodulation; Neuroprotective Agents; Receptors, CCR5
PubMed: 26782333
DOI: 10.1038/nrneurol.2015.248 -
Cancer Research Oct 2019Experiments of nature have revealed the peculiar importance of the G-protein-coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient... (Review)
Review
Experiments of nature have revealed the peculiar importance of the G-protein-coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient times. The resurgence of interest in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus on CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments regulatory T cell (Treg) differentiation and migration to sites of inflammation. The misexpression of CCR5 in epithelial cells, induced upon oncogenic transformation, hijacks this migratory phenotype. CCR5 reexpression augments resistance to DNA-damaging agents and is sufficient to induce cancer metastasis and "stemness". Recent studies suggest important cross-talk between CCR5 signaling and immune checkpoint function. Because CCR5 on Tregs serves as the coreceptor for human immunodeficiency virus (HIV) entry, CCR5-targeted therapeutics used in HIV, [small molecules (maraviroc and vicriviroc) and a humanized mAb (leronlimab)], are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein.
Topics: Animals; Carcinogenesis; Humans; Immunotherapy; Neoplasms; Receptors, CCR5
PubMed: 31292161
DOI: 10.1158/0008-5472.CAN-19-1167 -
Future Journal of Pharmaceutical... 2020Sexual transmission of HIV is the most common means of acquiring the disease. Topical microbicides have been investigated to prevent transmission. This study will use a...
BACKGROUND
Sexual transmission of HIV is the most common means of acquiring the disease. Topical microbicides have been investigated to prevent transmission. This study will use a specific entry inhibitor, maraviroc, and a nucleotide reverse transcriptase inhibitor (NRTI), tenofovir, a dual combination which will provide a synergist effect that can enhance the efficacy of HIV microbicides via a mucoadhesive dual compartment bigel. Bigel formulation via hydrogel organogel linkages were developed and evaluated for their physicochemical characteristics, safety, and anti-HIV efficacy. In vitro diffusion studies were performed with Franz diffusion cells having effective diffusion surface area of 1.76cm and receiver chamber volume of 15mL.
RESULT
The bigel formulations showed a viscosity ranging from 14179 to 14560 cPs and had a good spreadability and acidic pH in the range of 4.0 ± 0.34 to 5.2 ± 0.18. The bigel formulations showed good anti-HIV activity at a concentration of 0.1 μg/mL. The in vitro release study of maraviroc from the bigel formulations showed a release rate ranging from 2.675 to 3.838 μg/cm/min while the release rate for tenofovir ranged from 3.475 to 3.825 μg/cm/min. The bigel formulations were non-toxic to the human vagina as there was < 1 log change in viability.
CONCLUSION
This study successfully developed a dual compartment bigel containing maraviroc and tenofovir. BG C was found to be stable and safe towards vaginal and rectal epithelium, and it actively prevented HIV transmission. This bigel has the potential for long-term pre-exposure prophylaxis prevention of HIV transmission.
PubMed: 33241057
DOI: 10.1186/s43094-020-00093-3 -
Frontiers in Medicine 2023Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus...
Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants' response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.
PubMed: 36844201
DOI: 10.3389/fmed.2023.1122529 -
HIV-1 subtype C predicted co-receptor tropism in Africa: an individual sequence level meta-analysis.AIDS Research and Therapy Feb 2020Entry inhibitors, such as Maraviroc, hold promise as components of HIV treatment and/or pre-exposure prophylaxis in Africa. Maraviroc inhibits the interaction between... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Entry inhibitors, such as Maraviroc, hold promise as components of HIV treatment and/or pre-exposure prophylaxis in Africa. Maraviroc inhibits the interaction between HIV Envelope gp120 V3-loop and CCR5 coreceptor. HIV-1 subtype C (HIV-1-C) is predominant in Southern Africa and preferably uses CCR5 co-receptor. Therefore, a significant proportion of HIV-1-C CXCR4 utilizing viruses (X4) may compromise the effectiveness of Maraviroc. This analysis examined coreceptor preferences in early and chronic HIV-1-C infections across Africa.
METHODS
African HIV-1-C Envelope gp120 V3-loop sequences sampled from 1988 to 2014 were retrieved from Los Alamos HIV Sequence Database. Sequences from early infections (< 186 days post infection) and chronic infections (> 186 days post infection) were analysed for predicted co-receptor preferences using Geno2Pheno [Coreceptor] 10% FPR, Phenoseq-C, and PSSMsinsi web tools. V3-loop diversity was determined, and viral subtype was confirmed by phylogenetic analysis. National treatment guidelines across Africa were reviewed for Maraviroc recommendation.
RESULTS
Sequences from early (n = 6316) and chronic (n = 7338) HIV-1-C infected individuals from 10 and 15 African countries respectively were available for analyses. Overall, 518/6316 (8.2%; 95% CI 0.7-9.3) of early sequences were X4, with Ethiopia and Malawi having more than 10% each. For chronic infections, 8.3% (95% CI 2.4-16.2) sequences were X4 viruses, with Ethiopia, Tanzania, and Zimbabwe having more than 10% each. For sequences from early chronic infections (< 1 year post infection), the prevalence of X4 viruses was 8.5% (95% CI 2.6-11.2). In late chronic infections (≥ 5 years post infection), X4 viruses were observed in 36% (95% CI - 16.3 to 49.9), with two countries having relatively high X4 viruses: South Africa (43%) and Malawi (24%). The V3-loop amino acid sequence were more variable in X4 viruses in chronic infections compared to acute infections, with South Africa, Ethiopia and Zimbabwe showing the highest levels of V3-loop diversity. All sequences were phylogenetically confirmed as HIV-1-C and clustered according to their co-receptor tropism. In Africa, Maraviroc is registered only in South Africa and Uganda.
CONCLUSIONS
Our analyses illustrate that X4 viruses are present in significantly similar proportions in early and early chronic HIV-1 subtype C infected individuals across Africa. In contrast, in late chronic infections, X4 viruses increase 3-5 folds. We can draw two inferences from our observations: (1) to enhance the utility of Maraviroc in chronic HIV subtype C infections in Africa, prior virus co-receptor determination is needed; (2) on the flip side, research on the efficacy of CXCR4 antagonists for HIV-1-C infections is encouraged. Currently, the use of Maraviroc is very limited in Africa.
Topics: Drug Resistance, Multiple, Viral; Genotype; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Maraviroc; Phylogeny; Receptors, CXCR4; Receptors, HIV; Sequence Analysis, DNA; South Africa; Viral Tropism
PubMed: 32033571
DOI: 10.1186/s12981-020-0263-x -
Expert Opinion on Investigational Drugs Dec 2016The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug... (Review)
Review
The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists. Areas covered: This review aims to survey the current status of 'next generation' CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies. Expert opinion: The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.
Topics: Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclohexanes; Drug Design; HIV Infections; Humans; Imidazoles; Maraviroc; Sulfoxides; Triazoles
PubMed: 27791451
DOI: 10.1080/13543784.2016.1254615 -
Frontiers in Immunology 2022
Topics: HIV-1; Receptors, CCR5
PubMed: 36330512
DOI: 10.3389/fimmu.2022.1054430 -
Expert Opinion on Therapeutic Targets May 2024
Topics: Humans; Receptors, CCR5; Animals; Non-alcoholic Fatty Liver Disease; Molecular Targeted Therapy; CCR5 Receptor Antagonists
PubMed: 38857170
DOI: 10.1080/14728222.2024.2366880 -
BioRxiv : the Preprint Server For... Nov 2022In an effort to identify therapeutic intervention strategies for the treatment of COVID-19, we have investigated a selection of FDA-approved small molecules and...
In an effort to identify therapeutic intervention strategies for the treatment of COVID-19, we have investigated a selection of FDA-approved small molecules and biologics that are commonly used to treat other human diseases. A investigation into 18 small molecules and 3 biologics was conducted in cell culture and the impact of treatment on viral titer was quantified by plaque assay. The investigation identified 4 FDA-approved small molecules, Maraviroc, FTY720 (Fingolimod), Atorvastatin and Nitazoxanide that were able to inhibit SARS-CoV-2 infection. Confocal microscopy with over expressed S-protein demonstrated that Maraviroc reduced the extent of S-protein mediated cell fusion as observed by fewer multinucleate cells in the context of drug-treatment. Mathematical modeling of drug-dependent viral multiplication dynamics revealed that prolonged drug treatment will exert an exponential decrease in viral load in a multicellular/tissue environment. Taken together, the data demonstrate that Maraviroc, Fingolimod, Atorvastatin and Nitazoxanide inhibit SARS-CoV-2 in cell culture.
PubMed: 32817953
DOI: 10.1101/2020.08.12.246389