kappa opioid receptors in human microglia downregulate human immunodeficiency virus 1 expression.
Microglial cells, the resident macrophages of the brain, play an important role in the neuropathogenesis of human immunodeficiency virus type 1 (HIV-1), and recent studies suggest that opioid peptides regulate the function of macrophages from somatic tissues. We report herein the presence of kappa opioid receptors (KORs) in human fetal microglia and inhibition of HIV-1 expression in acutely infected microglial cell cultures treated with KOR ligands. Using reverse transcriptase-polymerase chain reaction and sequencing analyses, we found that mRNA for the KOR was constitutively expressed in microglia and determined that the nucleotide sequence of the open reading frame was identical to that of the human brain KOR gene. The expression of KOR in microglial cells was confirmed by membrane binding of [3H]U69,593, a kappa-selective ligand, and by indirect immunofluorescence. Treatment of microglial cell cultures with U50,488 or U69,593 resulted in a dose-dependent inhibition of expression of the monocytotropic HIV-1 SF162 strain. This antiviral effect of the kappa ligands was blocked by the specific KOR antagonist, nor-binaltrophimine. These findings suggest that kappa opioid agonists have immunomodulatory activity in the brain, and that these compounds could have potential in the treatment of HIV-1-associated encephalopathy.
Chao
C C
CC
Neuroimmunobiology and Host Defense Laboratory, Minneapolis Medical Research Foundation and University of Minnesota Medical School, 55404, USA.
Gekker
G
G
Hu
S
S
Sheng
W S
WS
Shark
K B
KB
Bu
D F
DF
Archer
S
S
Bidlack
J M
JM
Peterson
P K
PK
D000700:Analgesics / Q000378:metabolism; D001483:Base Sequence; D044482:Benzeneacetamides; D001921:Brain / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018076:DNA, Complementary; D004399:Dynorphins / Q000494:pharmacology; D005333:Fetus; D019084:Fluorescent Antibody Technique, Indirect; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D017628:Microglia / Q000187:drug effects / Q000502:physiology* / Q000821:virology*; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010446:Peptide Fragments / Q000494:pharmacology; D010799:Phycoerythrin; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000737:chemistry; D017473:Receptors, Opioid, kappa / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic; D014779:Virus Replication / Q000187:drug effects
D000700:Analgesics; D044482:Benzeneacetamides; D018076:DNA, Complementary; D010446:Peptide Fragments; D011759:Pyrrolidines; D012333:RNA, Messenger; D017473:Receptors, Opioid, kappa; D010799:Phycoerythrin; C026843:dynorphin (1-13); D004399:Dynorphins; C045444:U 69593