Delta-opioid suppression of human immunodeficiency virus-1 expression in T cells (Jurkat).
Delta-opioid receptor (DOR) transcripts and binding sites are expressed by lymphocytes and lymphoid cell lines from several species. Direct modulation of lymphocyte function through DORs affects T cell proliferation, interleukin-2 production, chemotaxis, and intracellular signaling. Moreover, in human DOR-transfected T cells (DOR-Ju.1), delta-opioids have been shown previously to mobilize intracellular calcium rapidly, to inhibit forskolin-stimulated cyclic AMP production, and to activate the mitogen-activated protein kinases ERKs 1 and 2. These observations led us to consider whether delta agonists modify T cell functions, thus affecting the expression of human immunodeficiency virus-1 (HIV-1) by CD4+ T cells. To test this hypothesis, DOR-Ju.1 cells, derived from Jurkat cells stably transfected with a cDNA encoding the neuronal DOR, were stimulated with deltorphin or benzamide, 4-[[2,5-dimethyl-4-(2-propenyl)-1-piperazinyl](3-methoxyphenyl)methyl]N- ,[2S[(S*),2alpha,5beta]]-(9Cl) (SNC-80) prior to the addition of HIV-1. Both deltorphin and SNC-80 concentration-dependently inhibited the production of p24 antigen, an index of HIV-1 expression. Inhibition was maximal with 10(-13)-10(-9) M SNC-80 (>60% reduction) or 10(-15)-10(-11) M deltorphin (>50% reduction). At higher concentrations, less inhibition of p24 antigen production was found. Naltrindole (NTI, 10(-11) M), a selective DOR antagonist, abolished the inhibitory effects of 10(-9) M SNC-80, whereas 10(-13) M NTI partially reversed the effect of SNC-80. Thus, activation of DORs expressed by CD4+ T cells significantly (P < 0.05) reduced the expression of HIV-1 by these cells. These findings suggest that opioid immunomodulation directed at host T cells may be adjunctive to standard antiviral approaches to HIV-1 infection.
Sharp
B M
BM
Immunomodulation Laboratory Institute for Brain and Immune Disorders, Minneapolis Medical Research Foundation, MN 55404, USA.
Gekker
G
G
Li
M D
MD
Chao
C C
CC
Peterson
P K
PK
D001549:Benzamides / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000187:drug effects* / Q000502:physiology; D013601:T-Lymphocytes / Q000821:virology*
D001549:Benzamides; D009842:Oligopeptides; D010879:Piperazines; D017465:Receptors, Opioid, delta; C059567:deltorphin; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009271:Naltrexone; C055382:naltrindole