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A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between
Nazira El-Hage1, Seth M Dever, Elizabeth M Podhaizer
1aDepartment of Pharmacology and Toxicology bDepartment of Medicinal Chemistry cInstitute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia, USA.
Objective:
We explored whether the opiate, morphine, affects the actions of maraviroc, as well as a recently synthesized bivalent derivative of maraviroc linked to an opioid antagonist, naltrexone, on HIV-1 entry in primary human glia.
Methods:
HIV-1 entry was monitored in glia transiently transfected with an LTR construct containing a luciferase reporter gene under control of a promoter for the HIV-1 transactivator protein Tat. The effect of maraviroc and the bivalent ligand with or without morphine on CCR5 surface expression and cytokine release was also explored.
Results:
Maraviroc inhibits HIV-1 entry into glial cells, whereas morphine negates the effects of maraviroc leading to a significant increase in viral entry. We also demonstrate that the maraviroc-containing bivalent ligand better inhibits R5-tropic viral entry in astrocytes than microglia compared to maraviroc when coadministered with morphine. Importantly, the inhibitory effects of the bivalent compound in astrocytes were not compromised by morphine. Exposure to maraviroc decreased the release of pro-inflammatory cytokines and restricted HIV-1-dependent increases in CCR5 expression in both astrocytes and microglia, whereas exposure to the bivalent had a similar effect in astrocytes but not in microglia. The CCR5-μ-opioid receptor (MOR) stoichiometric ratio varied among the two cell types with CCR5 expressed at much higher levels than MOR in microglia, which could explain the effectiveness of the bivalent ligand in astrocytes compared to microglia.
Conclusion:
A novel bivalent compound reveals fundamental differences in CCR5-MOR interactions and HIV-1 infectivity among glia, and has unique therapeutic potential in opiate abuse-HIV interactive comorbidity.
Insights
Morphine interferes with maraviroc
Area of Science:
- Neuroscience
- Virology
- Immunology
Background:
- HIV-1 entry into glial cells is a critical step in viral pathogenesis.
- Opioid use can impact HIV-1 infection and glial cell function.
- Maraviroc is an entry inhibitor targeting the CCR5 receptor.
Purpose of the Study:
- To investigate the effect of morphine on maraviroc's inhibition of HIV-1 entry into glia.
- To evaluate a novel bivalent compound linking maraviroc and naltrexone for HIV-1 entry inhibition.
- To explore differences in glial cell responses to these compounds.
Main Methods:
- HIV-1 entry assays in glia using a luciferase reporter system.
- Assessment of CCR5 surface expression and cytokine release.
- Co-administration of maraviroc, bivalent ligand, and morphine.
Main Results:
- Morphine negated maraviroc's inhibition of HIV-1 entry into glia.
- The bivalent compound inhibited viral entry in astrocytes more effectively than microglia, even with morphine.
- Differential CCR5-opioid receptor ratios in astrocytes and microglia influenced compound efficacy.
Conclusions:
- A novel bivalent compound demonstrates distinct CCR5-opioid receptor interactions in glia.
- This compound shows potential for treating co-occurring opiate abuse and HIV infection.
- Glial cell type influences HIV-1 infectivity and therapeutic responses.
