Norepinephrine accelerates HIV replication via protein kinase A-dependent effects on cytokine production.
To explore the role of sympathetic nervous system activation in HIV pathogenesis, we examined the effect of the neuroeffector molecule norepinephrine (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. This effect could be mimicked by protein kinase A (PKA) activators (forskolin or dibutyryl-cAMP) and abrogated by beta-adrenoreceptor antagonists or the PKA inhibitor rp-cAMP, indicating transduction via the adrenoreceptor signaling pathway. NE reduced cellular activation and altered the production of several HIV-modulating cytokines: IL-10 and IFN-gamma were markedly suppressed; TNF-alpha, IL-1beta, IL-2, IL-4, and IL-6 were mildly suppressed; and levels of IL-12 were not significantly altered. The addition of either exogenous IFN-gamma or IL-10 abrogated the effect of NE on virus production. Thus PKA-dependent suppression of cytokine production appears to mediate the enhancement of HIV-1 replication by NE.
University of California at Los Angeles AIDS Institute, Department of Medicine, UCLA School of Medicine 90095-1678, USA. coles@nicco.sscnet.ucla.edu
S W
SW
Cole
Y D
YD
Korin
J L
JL
Fahey
J A
JA
Zack
D000262:Adenylyl Cyclases / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000821:virology*; D008213:Lymphocyte Activation / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects*
D016207:Cytokines; D011943:Receptors, Adrenergic, beta; D016753:Interleukin-10; D007371:Interferon-gamma; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D009638:Norepinephrine