title: Mechanism of human immunodeficiency virus-induced complement expression in astrocytes and neurons.
abstract: The cerebral complement system is hypothesized to contribute to neurodegeneration in the pathogenesis of AIDS-associated neurological disorders. Our former results have shown that the human immunodeficiency virus (HIV) strongly induces the synthesis of complement factor C3 in astrocytes. This upregulation explains in vivo data showing elevated complement levels in the cerebrospinal fluid of patients with AIDS-associated neurological symptoms. Since inhibition of complement synthesis and activation in the brain may represent a putative therapeutic goal to prevent virus-induced damage, we analyzed in detail the mechanisms of HIV-induced modulation of C3 expression. HIV-1 increased the C3 levels in astrocyte culture supernatants from 30 to up to 400 ng/ml; signal transduction studies revealed that adenylate cyclase activation with upregulation of cyclic AMP is the central signaling pathway to mediate that increase. Furthermore, activity of protein kinase C is necessary for HIV induction of C3, since inhibition of protein kinase C by prolonged exposure to the phorbol ester tetradecanoyl phorbol acetate partly abolished the HIV effect. The cytokines tumor necrosis factor alpha and gamma interferon were not involved in mediating the HIV-induced C3 upregulation, since neutralizing antibodies had no effect. Besides whole HIV virions, the purified viral proteins Nef and gp41 are biologically active in upregulating C3, whereas Tat, gp120, and gp160 were not able to modulate C3 synthesis. Further experiments revealed that neurons were also able to respond on incubation with HIV with increased C3 synthesis, although the precise pattern was slightly different from that in astrocytes. This strengthens the hypothesis that HIV-induced complement synthesis represents an important mechanism for the pathogenesis of AIDS in the brain.
authors.affiliation: Institute of Hygiene and Social Medicine, University of Innsbruck Ludwig Boltzmann Institute for AIDS Research, Innsbruck, Austria. cornelia.speth@uibk.ac.at
authors.forename: Cornelia
authors.initials: C
authors.lastname: Speth
authors.forename: Thomas
authors.initials: T
authors.lastname: Schabetsberger
authors.forename: Iradji
authors.initials: I
authors.lastname: Mohsenipour
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stöckl
authors.forename: Reinhard
authors.initials: R
authors.lastname: Würzner
authors.forename: Heribert
authors.initials: H
authors.lastname: Stoiber
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lass-Flörl
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Dierich
mesh_terms: D000262:Adenylyl Cyclases / Q000494:pharmacology; D001253:Astrocytes / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D003176:Complement C3 / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism; D015693:Gene Products, nef / Q000494:pharmacology; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D009474:Neurons / Q000276:immunology* / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D003176:Complement C3; D015693:Gene Products, nef; D015700:HIV Envelope Protein gp41; D054311:nef Gene Products, Human Immunodeficiency Virus; D000242:Cyclic AMP; D000262:Adenylyl Cyclases