Abstract
Opioids may play an immunomodulatory role in the pathogenesis of human immunodeficiency virus-1 (HIV-1) infection. Recently, synthetic κ-opioid receptor (KOR) ligands have been found to have anti-human immunodeficiency virus type 1 activity in acutely infected brain macrophages. In the present study, we investigated whether the selective KOR ligand U50488 would exert such an anti-HIV-1 effect in acutely infected blood monocyte-derived macrophages (MDM). Treatment of acutely infected MDM with U50488 induced a concentration-dependent inhibition of HIV-1 expression. The dose-response relationship of U50488 was U-shaped with a peak effect observed at 10-13 M, which was evident at both 7 and 14 days post-infection. The KOR antagonist nor-binaltorphimine blocked the anti-HIV-1 effect of U50488 by 73%, indicating involvement of a KOR-mediated mechanism. Also, expression of KOR mRNA and binding activity with a fluorescence-labeled KOR ligand supported the existence of KOR on MDM. Antibodies to the β-chemokine, RANTES (regulated on activation normal T-cell expressed and secreted), but not to various other cytokines, blocked U50488 inhibition by 56% suggesting that the anti-HIV-1 effect of U50488 involved, in part, the production of RANTES by MDM. Taken together, these in vitro findings support the anti-HIV-1 property of U50488, and suggest that KOR ligands may have therapeutic potential for treating patients with acquired immunodeficiency syndrome.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 149-154 |
| Number of pages | 6 |
| Journal | Drug and alcohol dependence |
| Volume | 62 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 1 2001 |
Bibliographical note
Funding Information:The monocytotropic HIV-1 SF 162 strain was provided by the NIH AIDS Research and Reference Reagent Program (National Institute of Allergy and Infectious Diseases, Rockville, MD, USA). The KOR selective ligand U50488 was a gift of the Upjohn Company (Kalamazoo, MI, USA). The κ-selective antagonist nor-binaltorphimine (Nor-BNI) was provided kindly by P.S. Portoghese (University of Minnesota, Minneapolis, MN, USA). Other reagents were purchased from the indicated sources, antibodies to TNF-α, IL-1β, IL-6, and RANTES (R&D Systems Inc., Minneapolis, MN, USA); antibodies to macrophage CD14 receptor (Coulter, Miami, FL, USA); fetal bovine serum (FBS, HyClone Laboratories, Logan, UT, USA); dNTP mixture (Pharmacia, Piscataway, NJ, USA); Hepes-buffered balanced salt solution, RPMI-1640, penicillin (100 U/ml), streptomycin and all other culture reagents (Sigma Chemical Co., St. Louis, MO, USA).
Funding Information:
We thank Dr Fred Kravitz and Jean Bidlack for their invaluable assistance. This work was supported by US Public Health Service Grants DA09924, DA04381, and T32-DA07239 from the National Institute on Drug Abuse.
Keywords
- HIV/AIDS
- Immunobiology
- Macrophages
- RANTES
- U50,488
- κ-Opioid receptors
