UP-REGULATION OF HIV-1 EXPRESSION IN COCULTURES OF CHRONICALLY INFECTED PROMONOCYTES AND HUMAN BRAIN-CELLS BY DYNORPHIN

Using cocultures of human fetal brain cells and a chronically human im munodeficiency virus-1 (HIV-1)-infected promonocytic line U1, we inves tigated the effect of dynorphin, an endogenous opioid peptide found in the CNS, on upregulation of HIV-1 expression. Dynorphin and the synth etic kappa receptor agonist U50,488 promoted HIV-1 expression with a b ell-shaped concentration-response relationship in which maximal effect s were observed at 10(-13) and 10(-11) M, respectively. Pretreatment f or 30 min with the kappa receptor antagonist nor-binaltorphimine compl etely blocked the stimulatory effect of dynorphin and U50,488. The inv olvement of cytokines on HIV-1 expression was tested. Dynorphin-induce d upregulation of HIV-1 in the cocultures was largely blocked by antib odies to tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 but not by antibodies to IL-10. Also, dynorphin stimulated TNF-alpha and I L-6 in the brain cell cultures at both mRNA and protein levels, sugges ting the involvement of these cytokines in opioid-induced HIV-1 expres sion. These findings suggest that endogenous opioid peptides such as d ynorphin may have an immunomodulatory function in the CNS and could ac t as a cofactor in the neuropathogenesis of HIV-1.