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HIV/AIDS (Auckland, N.Z.) 2021To formulate and evaluate microspheres of the antiretroviral drugs maraviroc and tenofovir intended for a candidate vaginal microbicide and assess its effect on the...
Mucoadhesive Microspheres of Maraviroc and Tenofovir Designed for Pre-Exposure Prophylaxis of HIV-1: An in vitro Assessment of the Effect on Vaginal Lactic Acid Bacteria Microflora.
PURPOSE
To formulate and evaluate microspheres of the antiretroviral drugs maraviroc and tenofovir intended for a candidate vaginal microbicide and assess its effect on the vaginal lactic acid bacteria microflora.
METHODS
Ionic gelation technique was used to formulate maraviroc and tenofovir microspheres with subsequent characterization. The effect of varying concentrations of the polymer, crosslinking agent and the curing time on the outcome variables viz: particle size, mucoadhesion and encapsulation efficiency were investigated. Lactic acid bacteria were isolated from the vagina of healthy women using standard microbiologic methods. The analysis of their 16S rRNA sequence data identified and strains which were assigned GenBank accession numbers. The efficacy of the microspheres on HIV-1BaL strain was evaluated using TZM-bl indicator cells.
RESULTS
The optimal maraviroc and tenofovir microspheres had particle sizes of (434.82 µm and 456.18 µm), mucoadhesion of (93.3% and 90%) and encapsulation efficiency (92.80% and 78.9%) respectively. Maraviroc release kinetics followed a zero-order model and tenofovir was released via Higuchi model. The assay of a 1 mg/mL suspension of the microspheres on the strains of and showed a viability of 93.9% and 89.7%, respectively. There was a statistically significant difference between the mean absorbance readings of the test agent and that of the positive control (P = 0.001). The microspheres elicited a progressive decline in HIV infectivity until at a concentration of 1 μg/mL.
CONCLUSION
The antiretroviral drugs loaded in the microspheres, had good mucoadhesion which is a potential for prolonged residence time in the vagina. The antiretroviral drugs were adequately released from the microspheres and showed efficacy against the HIV-1 BaL virus strain. There was no significant disruption in the growth of the lactic acid bacteria which constitute valuable bacteria microflora of the vagina.
PubMed: 33859500
DOI: 10.2147/HIV.S291065 -
AIDS (London, England) Jan 2022Temsavir (TMR), the active agent of the gp120-directed attachment inhibitor fostemsavir (FTR), the CD4-directed attachment inhibitor ibalizumab (IBA), and the CCR5...
BACKGROUND
Temsavir (TMR), the active agent of the gp120-directed attachment inhibitor fostemsavir (FTR), the CD4-directed attachment inhibitor ibalizumab (IBA), and the CCR5 antagonist maraviroc (MVC) are antiretroviral agents that target steps in HIV-1 viral entry. Although mechanisms of inhibition of the three agents are different, it is important to understand whether there is potential for cross-resistance between these agents, as all involve interactions with gp120.
METHODS
Envelopes derived from plasma samples from participants in the BRIGHTE study who experienced protocol-derived virologic failure (PDVF) and were co-dosed with FTR and either IBA or MVC were analyzed for susceptibility to the agents. Also, CCR5-tropic MVC-resistant envelopes from the MOTIVATE trials were regenerated and studies were performed to understand whether susceptibility to multiple agents were linked.
RESULTS
The cloned envelopes exhibited reduced susceptibility to TMR and resistance to the co-dosed agent. At PDVF, emergent or preexisting amino acid substitutions were present at TMR positions of interest. When amino acid substitutions at these positions were reverted to the consensus sequence, full susceptibility to TMR was restored without effecting resistance to the co-dosed agent. In addition, five envelopes from MOTIVATE were regenerated and exhibited R5-tropic-MVC-resistance. Only one exhibited reduced susceptibility to TMR and it contained an M426L polymorphism. When reverted to 426M, full sensitivity for TMR was restored, but it remained MVC resistant.
CONCLUSION
The data confirm that decreased susceptibility to TMR and resistance to IBA or MVC are not linked and that there is no cross-resistance between either of these two agents and FTR.
Topics: Anti-HIV Agents; Antibodies, Monoclonal; CCR5 Receptor Antagonists; Cyclohexanes; Drug Resistance, Viral; HIV Envelope Protein gp120; HIV Infections; Humans; Maraviroc
PubMed: 34628442
DOI: 10.1097/QAD.0000000000003097 -
Journal of Basic and Clinical... Jun 2021Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist...
OBJECTIVES
Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles.
METHODS
The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1-BX471, BX513, BI639667; CCR2-RS504393, INCB3284; CCR3-SB328437; and CCR4-AZD2098, and C021; CCR5-Maraviroc; CCR10-BI6901. The pan-α-adrenoceptor antagonist prazosin was used as control.
RESULTS
Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine.
CONCLUSIONS
Our data suggest that CCR antagonists should be screened for cross-reactivity with α-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Phenylephrine; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Receptors, Chemokine; beta-Arrestins
PubMed: 34144642
DOI: 10.1515/jbcpp-2020-0523 -
Journal of Virology Feb 2018Residual viremia is common during antiretroviral therapy (ART) and could be caused by ongoing low-level virus replication or by release of viral particles from infected... (Randomized Controlled Trial)
Randomized Controlled Trial
Residual viremia is common during antiretroviral therapy (ART) and could be caused by ongoing low-level virus replication or by release of viral particles from infected cells. ART intensification should impact ongoing viral propagation but not virion release. Eighteen acutely infected men were enrolled in a randomized controlled trial and monitored for a median of 107 weeks. Participants started ART with ( = 9) or without ( = 9) intensification with maraviroc (MVC) within 90 days of infection. Levels of HIV DNA and cell-free RNA were quantified by droplet digital PCR. Deep sequencing of C2-V3 , , and (454 Roche) was performed on longitudinally collected plasma and peripheral blood mononuclear cell (PBMC) samples while on ART. Sequence data were analyzed for evidence of evolution by (i) molecular diversity analysis, (ii) nonparametric test for panmixia, and (iii) tip date randomization within a Bayesian framework. There was a longitudinal decay of HIV DNA after initiation of ART with no difference between MVC intensification groups (-0.08 ± 0.01 versus -0.09 ± 0.01 log copies/week in MVC versus MVC groups; = 0.62). All participants had low-level residual viremia (median, 2.8 RNA copies/ml). Across participants, medians of 56 (interquartile range [IQR], 36 to 74), 29 (IQR, 25 to 35), and 40 (IQR, 31 to 54) haplotypes were generated for , , and regions, respectively. There was no clear evidence of viral evolution during ART and no difference in viral diversity or population structure from individuals with or without MVC intensification. Further efforts focusing on elucidating the mechanism(s) of viral persistence in various compartments using recent sequencing technologies are still needed, and potential low-level viral replication should always be considered in cure strategies. Residual viremia is common among HIV-infected people on ART. It remains controversial if this viremia is a consequence of propagating infection. We hypothesized that molecular evolution would be detectable during viral propagation and that therapy intensified with the entry inhibitor maraviroc would demonstrate less evolution. We performed a randomized double-blinded treatment trial with 18 acutely infected men (standard ART versus standard ART plus maraviroc). From longitudinally collected blood plasma and cells, levels of HIV DNA and cell-free HIV RNA were quantified by droplet digital PCR, and HIV DNA (, , and coding regions) was deep sequenced (454 Roche). Investigating people who started ART during the earliest stages of their HIV infection, when viral diversity is low, provides an opportunity to detect evidence of viral evolution. Despite using a battery of analytical techniques, no clear and consistent evidence of viral propagation for over 90 weeks of observation could be discerned.
Topics: Adult; Antiretroviral Therapy, Highly Active; Bayes Theorem; CCR5 Receptor Antagonists; California; Cyclohexanes; DNA, Viral; Double-Blind Method; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; RNA, Viral; Triazoles; Viral Load; Viremia; Virus Replication; Young Adult
PubMed: 29142136
DOI: 10.1128/JVI.01589-17 -
Briefings in Bioinformatics May 2022Inhibition of host protein functions using established drugs produces a promising antiviral effect with excellent safety profiles, decreased incidence of resistant...
Inhibition of host protein functions using established drugs produces a promising antiviral effect with excellent safety profiles, decreased incidence of resistant variants and favorable balance of costs and risks. Genomic methods have produced a large number of robust host factors, providing candidates for identification of antiviral drug targets. However, there is a lack of global perspectives and systematic prioritization of known virus-targeted host proteins (VTHPs) and drug targets. There is also a need for host-directed repositioned antivirals. Here, we integrated 6140 VTHPs and grouped viral infection modes from a new perspective of enriched pathways of VTHPs. Clarifying the superiority of nonessential membrane and hub VTHPs as potential ideal targets for repositioned antivirals, we proposed 543 candidate VTHPs. We then presented a large-scale drug-virus network (DVN) based on matching these VTHPs and drug targets. We predicted possible indications for 703 approved drugs against 35 viruses and explored their potential as broad-spectrum antivirals. In vitro and in vivo tests validated the efficacy of bosutinib, maraviroc and dextromethorphan against human herpesvirus 1 (HHV-1), hepatitis B virus (HBV) and influenza A virus (IAV). Their drug synergy with clinically used antivirals was evaluated and confirmed. The results proved that low-dose dextromethorphan is better than high-dose in both single and combined treatments. This study provides a comprehensive landscape and optimization strategy for druggable VTHPs, constructing an innovative and potent pipeline to discover novel antiviral host proteins and repositioned drugs, which may facilitate their delivery to clinical application in translational medicine to combat fatal and spreading viral infections.
Topics: Antiviral Agents; Dextromethorphan; Humans; Influenza A virus
PubMed: 35238349
DOI: 10.1093/bib/bbac047 -
The Journal of Antimicrobial... Feb 2022Tenofovir disoproxil fumarate-containing pre-exposure prophylaxis (PrEP) has been associated with decreases in bone mineral density (BMD), but the bone effects of other... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tenofovir disoproxil fumarate-containing pre-exposure prophylaxis (PrEP) has been associated with decreases in bone mineral density (BMD), but the bone effects of other non-tenofovir disoproxil fumarate candidate PrEP regimens are not well described.
METHODS
The HPTN 069/ACTG A5305 study randomized 406 US cisgender men and transgender women, and 188 cisgender women at risk for HIV infection to one of four double-blinded regimens: (i) maraviroc; (ii) maraviroc + emtricitabine; (iii) maraviroc + tenofovir disoproxil fumarate; or (iv) tenofovir disoproxil fumarate + emtricitabine. BMD was measured in a subset of participants at the lumbar spine (LS) and hip by dual-energy X-ray absorptiometry (DXA) at baseline and 48 weeks. Percentage change in LS and hip BMD was compared between the tenofovir disoproxil fumarate- and non-tenofovir disoproxil fumarate-containing arms by Wilcoxon rank-sum tests and multiple linear regression adjusting for sex, race and baseline BMI.
RESULTS
At baseline (n = 307), the median age was 33 years, 56% male and 43% black. At the hip, the median percentage change in BMD at 48 weeks was -1.05% in the tenofovir disoproxil fumarate arms and 0.0% in the non-tenofovir disoproxil fumarate arms (between group P = 0.001). No interaction by sex was observed. The median percentage change in LS BMD was not different between arms.
CONCLUSIONS
Tenofovir disoproxil fumarate-containing PrEP was associated with significantly greater bone loss compared with maraviroc ± emtricitabine PrEP at the hip, but not the LS. The BMD changes at the hip were similar in magnitude in men and women.
Topics: Adult; Anti-HIV Agents; Double-Blind Method; Emtricitabine; Female; HIV Infections; Humans; Male; Maraviroc; Tenofovir
PubMed: 34791296
DOI: 10.1093/jac/dkab400 -
Molecular Oncology Jan 2024Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a...
Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a microenvironment that promotes cancer cell metastasis in the peritoneum. Here, we investigated the roles of lactosylceramide alpha-2,3-sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome-mediated premetastatic niche in peritoneal milky spots (MSs). Exosomes secreted from ST3G5 cancer cells (ST3G5 -cExos) were found to contain high levels of hypoxia-inducible factor 1-alpha (HIF1α) and accumulated in MSs via uptake in macrophages (MΦs) owing to increased expression of sialic acid-binding Ig-like lectin 1 (CD169; also known as SIGLEC1). ST3G5 -cExos induced pro-inflammatory cytokines and glucose metabolic changes in MΦs, and the interaction of these MΦs with PMCs promoted mesothelial-mesenchymal transition (MMT) in PMCs, thereby generating αSMA myofibroblasts. ST3G5 -cExos also increased the expression of immune checkpoint molecules and T-cell exhaustion in MSs, which accelerated metastasis to the omentum. These events were prevented following ST3G5 depletion in cancer cells. Mechanistically, ST3G5 -cExos upregulated chemokines, including CC-chemokine ligand 5 (CCL5), in recipient MΦs and dendritic cells (DCs), which induced MMT and immunosuppression via activation of signal transducer and activator of transcription 3 (STAT3). Maraviroc, a C-C chemokine receptor type 5 (CCR5) antagonist, prevented ST3G5 -cExo-mediated MMT, T-cell suppression, and metastasis in MSs. Our results suggest ST3G5 as a suitable therapeutic target for preventing cExo-mediated peritoneal dissemination.
Topics: Humans; Peritoneum; Exosomes; Cell Communication; Biological Transport; Neoplasms
PubMed: 37716915
DOI: 10.1002/1878-0261.13524 -
Aging Apr 2020As age increases, the risk of developing fragility also increases. Improving the knowledge of frailty could contribute to maintaining the functional ability of elderly...
BACKGROUND
As age increases, the risk of developing fragility also increases. Improving the knowledge of frailty could contribute to maintaining the functional ability of elderly people. Interleukin (IL)-10 homozygous knockout mice (IL-10 [IL10KO]) constitute an excellent tool for the study of frailty. Because patients with frailty demonstrate an overexpression of CCR5, rapamycin (RAPA) and/or maraviroc (MVC), two molecules able to decrease CCR5 expression, were evaluated.
RESULTS
Muscle myostatin was reduced in all the therapeutic groups but the MVC group (p <0.001 for RAPA and MVC-RAPA) and in serum samples (p <0.01 for all the groups). Serum CK levels were also significantly lower in MVC and RAPA groups (p <0.01 in both cases). Lower AST levels were observed in all the therapeutic groups (p <0.05 for all of them). The apoptotic effector caspase-3 was significantly lower in MVC and RAPA groups (p<0.05 in both cases). Combined treatment with MVC-RAPA showed a synergistic increase in p-AKT, p-mTOR and SIRT1 levels.
CONCLUSIONS
MVC and RAPA show a protective role in some factors involved in frailty. More studies are needed to prove their clinical applications.
MATERIAL AND METHODS
Eighty male homozygous IL10KOs were randomly assigned to one of 4 groups (n= 20): i) IL10KO group (IL10KO); ii) IL10KO receiving MVC in drinking water (MVC group), iii) IL10KO receiving RAPA in drinking water (RAPA group), and finally, iv) MVC-RAPA group that received MVC and RAPA in drinking water. Blood and muscle samples were analysed. Survival analysis, frailty index calculation, and functional assessment were also performed.
Topics: Aging; Animals; Cytokines; Disease Models, Animal; Frailty; Interleukin-10; Male; Maraviroc; Mice; Mice, Knockout; Muscle, Skeletal; Random Allocation; Receptors, Chemokine; Sirolimus; Survival Rate
PubMed: 32353830
DOI: 10.18632/aging.103167 -
Molecular Cancer Research : MCR Jul 2023Cancer-associated fibroblasts (CAF) can promote tumor growth, metastasis, and therapeutic resistance in esophageal squamous cell carcinoma (ESCC), but the mechanisms of...
UNLABELLED
Cancer-associated fibroblasts (CAF) can promote tumor growth, metastasis, and therapeutic resistance in esophageal squamous cell carcinoma (ESCC), but the mechanisms of action remain elusive. Our objective was to identify secreted factor(s) that mediate the communication between CAFs and ESCC tumor cells with the aim of identifying potential druggable targets. Through unbiased cytokine arrays, we have identified CC motif chemokine ligand 5 (CCL5) as a secreted factor that is increased upon co-culture of ESCC cells and CAFs, which we replicated in esophageal adenocarcinoma (EAC) with CAFs. Loss of tumor-cell-derived CCL5 reduces ESCC cell proliferation in vitro and in vivo and we propose this is mediated, in part, by a reduction in ERK1/2 signaling. Loss of tumor-derived CCL5 reduces the percentage of CAFs recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists, namely Maraviroc. Maraviroc treatment reduced tumor volume, CAF recruitment, and ERK1/2 signaling in vivo, thus, mimicking the effects observed with genetic loss of CCL5. High CCL5 or CCR5 expression is associated with worse prognosis in low-grade esophageal carcinomas.
IMPLICATIONS
These data highlight the role of CCL5 in tumorigenesis and the therapeutic potential of targeting the CCL5-CCR5 axis in ESCC.
Topics: Humans; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Proliferation; Chemokine CCL5; Chemokines; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Fibroblasts; Ligands; Maraviroc; Animals
PubMed: 37027010
DOI: 10.1158/1541-7786.MCR-22-0872 -
The Journal of Allergy and Clinical... Jan 2022Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1...
BACKGROUND
Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1 inflammation manifesting with IFN-γ expression and variable type 2 responses.
OBJECTIVE
We investigated the role of the chemotactic receptors C-X-C chemokine receptor 3 (CXCR3) and C-C chemokine receptor 5 (CCR5) in establishing type 1 inflammation in SA.
METHODS
Bronchoalveolar lavage microarray data from the Severe Asthma Research Program I/II were analyzed for pathway expression and paired with clinical parameters. Wild-type, Cxcr3, and Ccr5 mice were exposed to a type 1-high SA model with analysis of whole lung gene expression and histology. Wild-type and Cxcr3 mice were treated with a US Food and Drug Administration-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression, and histology.
RESULTS
A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression was correlated with CXCR3 and CCR5 expression, but in Cxcr3 and Ccr5 mice type 1 inflammation was preserved in a murine SA model, most likely owing to compensation by the other pathway. Incorporation of maraviroc into the experimental model blunted airway hyperreactivity despite only mild effects on lung inflammation.
CONCLUSIONS
IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. Although these pathways provide redundancy for establishing type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in individuals with type 1-high asthma.
Topics: Adult; Airway Resistance; Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; CCR5 Receptor Antagonists; Female; Humans; Inflammation; Interferon-gamma; Male; Maraviroc; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Receptors, CCR5; Receptors, CXCR3; Respiratory Mucosa; Severity of Illness Index; Young Adult; Mice
PubMed: 34146578
DOI: 10.1016/j.jaci.2021.05.044