U50488 inhibits HIV-1 expression in acutely infected monocyte-derived macrophages.
Opioids may play an immunomodulatory role in the pathogenesis of human immunodeficiency virus-1 (HIV-1) infection. Recently, synthetic kappa-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 beta-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.
Chao
C C
CC
Institute for Brain and Immune Disorders, Minneapolis Medical Research Foundation, Hennepin County Medical Center and the University of Minnesota Medical School, Minneapolis, MN 55404, USA.
Gekker
G
G
Sheng
W S
WS
Hu
S
S
Peterson
P K
PK
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000008:administration & dosage / Q000494:pharmacology*; D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism*; D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005453:Fluorescence; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000821:virology*; D009000:Monocytes / Q000187:drug effects* / Q000821:virology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018712:Analgesics, Non-Narcotic; D018946:Chemokine CCL5; D016207:Cytokines; D012333:RNA, Messenger; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer