Association of Polymorphisms of the Mu Opioid Receptor Gene with the Severity of HIV Infection and Response to HIV Treatment

Proudnikov, Dmitri; Randesi, Matthew; Levran, Orna; Crystal, Howard; Dorn, Magdalena; Ott, Jürg; Ho, Ann; Kreek, Mary Jeanne

doi:10.1093/infdis/jis264

Cited by 15 publications

(12 citation statements)

References 49 publications

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“…The latest cART era evidence indicates that preferential heroin abuse exacerbates HIV-associated neurocognitive disorders (HAND) [70-72] and peripheral neuropathies [73]. While some clinical studies report minimal or no neurocognitive differences between HIV ± opiate abuse [74, 75], these studies fail to consider critical genetic, pharmacokinetic, and pharmacodynamic differences among opiate abusers [76-78]. Here we show that an opiate can limit the antiretroviral effects of maraviroc, while the coordinated blockade of MOR and CCR5, using this novel bivalent compound, has considerable potential for development as a therapeutic strategy or as a molecular tool to study HIV-GPCR co-receptor interactions.…”

Section: Discussionmentioning

confidence: 99%

A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between human astroglia and microglia

El‐Hage¹,

Dever²,

Podhaizer³

et al. 2013

Aids

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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 ± morphine on CCR5 surface expression and cytokine release was also explored. Results Maraviroc inhibits HIV-1 entry into glial cells, while 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, while exposure to the bivalent had similar effect in astrocytes but not in microglia. CCR5-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.

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Section: Discussionmentioning

confidence: 99%

A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between human astroglia and microglia

El‐Hage¹,

Dever²,

Podhaizer³

et al. 2013

Aids

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“…Moreover, polymorphisms in the μ -opioid receptor (MOR) gene (OPRM1) have been suggested to alter the severity of HIV-1 infection and individual responsiveness to combination antiretroviral therapy (Proudnikov et al, 2012). The increases in HIV-1 pathogenesis caused by opioid abuse have largely been attributed to opioid suppression of immune function (Adler et al, 1993; Carr and Serou, 1995; Peterson et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Morphine efficacy is altered in conditional HIV-1 Tat transgenic mice

Fitting

Scoggins

et al. 2012

European Journal of Pharmacology

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Opiate abuse reportedly can exaggerate complications of human immunodeficiency virus type-1 (HIV-1) infection in the central nervous system (CNS), while opiate drugs are often indicated in the treatment of HIV-1-related neuropathic pain. Despite this quandary, few studies have assessed the relationship between the duration or extent of HIV-1 infection and the intrinsic neurobehavioral responsiveness to opioids. To address this problem, doxycycline (DOX)-inducible HIV-Tat1-86 transgenic mice were used as a model for HIV-1-associated neurocognitive disorders, which permitted the regulation of Tat exposure and duration. The effects of continuous Tat induction on the activity of morphine were examined at weekly intervals using standard behavioral assays for nociception and motor function. In the spinal cord, Tat mRNA levels did not increase until the second and third weeks following induction, which corresponded to a significant loss of morphine antinociception as assessed in the tail-flick test. Alternatively, in the striatum, sustained increases in Tat mRNA expression during the second week of induction coincided with significant decreases in rotarod performance and interactions with morphine. Importantly, the behavioral effects of morphine differed depending on the timing and location of Tat expression; with increases in Tat transcript levels in the spinal cord and striatum corresponding to significant alterations in morphine-dependent nociception and rotarod performance, respectively. Assuming Tat levels contribute to the clinical manifestations of HIV-1, the results suggest that regional differences in viral load and opioid phenotype might influence the nature and degree that opiate responsiveness is altered in HIV-1 infected individuals.

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“…From this and our previous study, we speculate that out of the MOR-1, MOR-1A, MOR-1X, and MOR-1K variants, MOR-1K is most likely to play a major role in HIV disease pathology. However, as HIV-infected individuals with the A118G (N40D) polymorphism located in exon 1 of the receptor have more severe disease progression [63], certain C-terminal MOR variants must also play a role. Characterization of the particular MOR splice variants involved and their molecular interactions could lead to unique strategies for tailored drug design directed towards targeting specific MOR variants.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of the alternatively spliced OPRM1 isoform μ-opioid receptor-1K in HIV-infected individuals

Dever¹,

Costin²,

et al. 2014

Aids

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Objective We previously examined the expression of specific C-terminal μ-opioid receptor (MOR) splice variants in human central nervous system cell types and HIV-infected brain tissue from subjects with neurocognitive impairment ± HIV encephalitis (HIVE). In the present study, we examined the N-terminal splice variant MOR-1K which mediates excitatory cellular signaling. Methods and Results We found segregation of expression ranging from undetectable to seemingly exclusive across nervous system cell types compared to the pool of C-terminal MOR splice variants using RT-PCR. Expression of MOR-1K mRNA was also increased in HIV-infected subjects with combined neurocognitive impairment and HIVE compared to the other groups. MOR-1K expression correlated with the level of subject neurocognitive impairment whereas the pool of C-terminal MOR splice variants did not. HIVE was also associated with increased expression of the inflammatory mediators MCP-1, MCP-2, and RANTES, but not the host HIV co-receptors CXCR4 and CCR5 or the CD4 receptor, using qRT-PCR. Network analysis of microarray data from these same subjects revealed filamin A (FLNA) as a possible interaction partner with MOR-1K, and FLNA gene expression was also found to be upregulated in HIVE using qRT-PCR. Overexpression of filamin A in HEK293 cells redistributed MOR-1K from intracellular compartments to the cell surface. Conclusion These results suggest that HIVE, and neurocognitive impairment depending on its severity, are associated with enhanced MOR-1K signaling through both increased expression and trafficking to the cell surface, which may alter the contribution of MOR receptor isoforms and exacerbate the effects of MOR activation in neuroAIDS.

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Association of Polymorphisms of the Mu Opioid Receptor Gene with the Severity of HIV Infection and Response to HIV Treatment

Abstract: OPRM1 polymorphisms may alter the severity of HIV infection before and after HAART.

Cited by 15 publications

References 49 publications

A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between human astroglia and microglia

A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-μ-opioid receptor interactions between human astroglia and microglia

Morphine efficacy is altered in conditional HIV-1 Tat transgenic mice

Differential expression of the alternatively spliced OPRM1 isoform μ-opioid receptor-1K in HIV-infected individuals

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