HIV increases the release of dickkopf-1 protein from human astrocytes by a Cx43 hemichannel-dependent mechanism

Juan Andres Orellana, Juan Carlos Sáez, Michael Vander Lann Bennett, Joan Weinberger Berman, Susan Morgello, Eliseo Alberto Eugenin

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)752-763
Number of pages12
JournalJournal of Neurochemistry
Volume128
Issue number5
DOIs
StatePublished - Mar 2014

Keywords

  • HIV
  • dementia
  • gap junctions
  • neuroAIDS

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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