NOREPINEPHRINE ACCELERATES HIV REPLICATION VIA PROTEIN-KINASE A-DEPENDENT EFFECTS ON CYTOKINE PRODUCTION

To explore the role of sympathetic nervous system activation in HIV pa thogenesis, we examined the effect of the neuroeffector molecule norep inephrine (NE) on HIV-1 replication in quiescently infected PBMCs that were subsequently activated with Abs to CD3 and CD28. NE accelerated HIV-1 replication at concentrations ranging from 10(-8) to 10(-5) M. T his effect could be mimicked by protein kinase A (PKA) activators (for skolin or dibutyryl-cAMP) and abrogated by beta-adrenoreceptor antagon ists or the PKA inhibitor rp-cAMP, indicating transduction via the adr enoreceptor signaling pathway, NE reduced cellular activation and alte red the production of several HIV-modulating cytokines: IL-10 and IFN- gamma were markedly suppressed; TNF-alpha, IL-1 beta, IL-2, IL-4, and IL-6 mere mildly suppressed; and levels of IL-12 were nest significant ly altered. The addition of either exogenous IFN-gamma or IL-10 abroga ted tale effect of NE on virus production Thus PKA-dependent suppressi on of cytokine production appears to mediate the enhancement of HIV-1 replication by NE.