Kappa-opioid potentiation of tumor necrosis factor-alpha-induced anti-HIV-1 activity in acutely infected human brain cell cultures.
Opioids have been postulated to play an immunomodulatory role in the pathogenesis of HIV-1. Synthetic kappa-opioid receptor (KOR) ligands have been found to inhibit HIV-1 expression in acutely infected microglial cell cultures. We recently found that interleukin(IL)-1beta and tumor necrosis factor(TNF)-alpha have antiviral effects in acutely infected mixed glial/neuronal cell cultures. In the present study, we investigated whether selective KOR ligands would exert antiviral effects in acutely infected brain cell cultures. While the KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benze neaceamide methanesulfonate (U50,488) alone had little anti-HIV-1 activity, this opioid potentiated in a concentration-dependent manner the antiviral activity of TNF-alpha, but not of IL-1beta. The potentiating effect of U50,488 was detected after a 6-hr pretreatment and peaked at 24 hr. The KOR antagonist nor-binaltorphimine completely blocked the potentiating effect of U50,488, suggesting the involvement of a KOR-mediated mechanism. Antibodies to TNF-alpha completely blocked the potentiating effect of U50,488, suggesting a critical role for TNF-alpha. Antibodies to IL-1beta blocked the potentiating effect of U50,488, suggesting that IL-1beta was released following U50,488 treatment, which might contribute to the potentiating effect of U50,488. These in vitro findings support the notion that synthetic kappa-opioids could be considered as potential adjunctive therapeutic agents in HIV-1-related brain disease.
Chao
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Institute for Brain and Immune Disorders, Minneapolis Medical Research Foundation and the University of Minnesota Medical School, 55404, USA. chaox002@maroon.tc.umn.edu
Gekker
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Hu
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Kravitz
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Peterson
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D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001921:Brain / Q000821:virology*; D002478:Cells, Cultured; D004357:Drug Synergism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000998:Antiviral Agents; D007375:Interleukin-1; D017473:Receptors, Opioid, kappa; D014409:Tumor Necrosis Factor-alpha; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer