Synthetic K-opioid receptor (KOR) agonists have been shown to suppress HIV-
1 expression in acutely infected macrophages. In the present study, we exam
ined the effects of the KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1 -pyro
lidinyl)cyclohexyl] benzeneaceamide methanesulfonate (U50,488) on HIV-1 exp
ression in CD4(+) lymphocytes, the main target cell of this virus. When U50
,488 was added to activated CD4(+) lymphocytes, HIV-1 expression was inhibi
ted in a concentration- and time-dependent manner with maximal suppression
( approximate to 60%) at 10(-7) M U50,488, The KOR selective antagonist nor
-binaltorphimine (nor-BNI) had no effect by itself on viral expression but
blocked the antiviral property of U50,488, suggesting that U50,488 was acti
ng via a KOR-related mechanism. Support for the involvement of KOR was prov
ided by the findings that 34% of activated CD4(+) lymphocytes were positive
for KOR, using an immunofluorescence technique, and that seven additional
synthetic KOR ligands also inhibited HIV-1 expression. The results of this
study broaden understanding of the antiviral properties of KOR ligands to i
nclude cells outside of the nervous system and suggest a potential role for
these agents in the treatment of HIV-I infection. (C) 2001 Elsevier Scienc
e Inc. All rights reserved.