title: HIV increases the release of dickkopf-1 protein from human astrocytes by a Cx43 hemichannel-dependent mechanism.
abstract: Human immunodeficiency virus-1 (HIV) is a public health issue and a major complication of the disease is NeuroAIDS. In vivo, microglia/macrophages are the main cells infected. However, a low but significant number of HIV-infected astrocytes has also been detected, but their role in the pathogenesis of NeuroAIDS is not well understood. Our previous data indicate that gap junction channels amplify toxicity from few HIV-infected into uninfected astrocytes. Now, we demonstrated that HIV infection of astrocytes results in the opening of connexin43 hemichannels (HCs). HIV-induced opening of connexin43 HCs resulted in dysregulated secretion of dickkopf-1 protein (DKK1, a soluble wnt pathway inhibitor). Treatment of mixed cultures of neurons and astrocytes with DKK1, in the absence of HIV infection, resulted in the collapse of neuronal processes. HIV infection of mixed cultures of human neurons and astrocytes also resulted in the collapse of neuronal processes through a DKK1-dependent mechanism. In addition, dysregulated DKK1 expression in astrocytes was observed in human brain tissue sections of individuals with HIV encephalitis as compared to tissue sections from uninfected individuals. Thus, we demonstrated that HIV infection of astrocytes induces dysregulation of DKK1 by a HC-dependent mechanism that contributes to the brain pathogenesis observed in HIV-infected individuals. Our studies demonstrated that HIV infection of astrocytes, despite minimal replication and a low number of infected cells, induces dysregulation of DKK1 secretion by a Cx43 hemichannel (HC)-dependent mechanism. Enhanced DKK1 secretion in response to HIV infection of glial cells compromised formation and stability of neuronal processes, similar to the synaptic compromise observed in HIV-infected individuals. In addition, analysis of human brain tissue sections obtained from encephalitic individuals also shows enhanced expression of DKK1 in astrocytes. Our data provide a novel mechanism by which HIV infection of glial cells participate in the pathogenesis of brain dysfunction observed in HIV-infected individuals. LRP5 = Low-density lipoprotein receptor-related protein 5.
authors.affiliation: Public Health Research Institute (PHRI), Rutgers New Jersey Medical School, Rutgers The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Juan Andres
authors.initials: JA
authors.lastname: Orellana
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Sáez
authors.forename: Michael Vander Lann
authors.initials: MV
authors.lastname: Bennett
authors.forename: Joan Weinberger
authors.initials: JW
authors.lastname: Berman
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.forename: Eliseo Alberto
authors.initials: EA
authors.lastname: Eugenin
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism; D061251:Primary Cell Culture; D019707:Receptors, Chemokine / Q000378:metabolism; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D018031:Connexin 43; C501126:DKK1 protein, human; D016655:HIV Core Protein p24; D036341:Intercellular Signaling Peptides and Proteins; D019707:Receptors, Chemokine; D051153:Wnt Proteins
keywords: HIV; dementia; gap junctions; neuroAIDS