Using cocultures of human fetal brain cells and a chronically human immunodeficiency virus-1 (HIV-1)-infected promonocytic line U1, we investigated the effect of dynorphin, an endogenous opioid peptide found in the CNS, on upregulation of HIV-1 expression. Dynorphin and the synthetic κ receptor agonist U50,488 promoted HIV-1 expression with a bell-shaped concentration-response relationship in which maximal effects were observed at 10-13 and 10-11 M, respectively. Pretreatment for 30 min with the κ receptor antagonist nor-binaltorphimine completely blocked the stimulatory effect of dynorphin and U50,488. The involvement of cytokines on HIV-1 expression was tested. Dynorphininduced upregulation of HIV-1 in the cocultures was largely blocked by antibodies to tumor necrosis factor (TNF)-α and interleukin (IL)-6 but not by antibodies to IL-10. Also, dynorphin stimulated TNF-α and IL-6 in the brain cell cultures at both mRNA and protein levels, suggesting the involvement of these cytokines in opioid-induced HIV-1 expression. These findings suggest that endogenous opioid peptides such as dynorphin may have an immunomodulatory function in the CNS and could act as a cofactor in the neuropathogenesis of HIV-1.
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Acknowledgements-We thank Drs. Fred Kravitz. W. Robert Anderson, and Monica Tsang for their invaluable assistance, and Stacey Ulen for help in the preparation of the manuscript. This study was supported in part by United States Public Health Services Grants DA-04381, DA-01533. and T32-DA-07239.
- human immunodeficiency virus-1