HIV-tat alters Connexin43 expression and trafficking in human astrocytes: Role in NeuroAIDS

Joan W. Berman, Loreto Carvallo, Clarisa M. Buckner, Aimée Luers, Lisa Prevedel, Michael V. Bennett, Eliseo Eugenin

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: HIV-associated neurocognitive disorders (HAND) are a major complication in at least half of the infected population despite effective antiretroviral treatment and immune reconstitution. HIV-associated CNS damage is not correlated with active viral replication but instead is associated with mechanisms that regulate inflammation and neuronal compromise. Our data indicate that one of these mechanisms is mediated by gap junction channels and/or hemichannels. Normally, gap junction channels shutdown under inflammatory conditions, including viral diseases. However, HIV infection upregulates Connexin43 (Cx43) expression and maintains gap junctional communication by unknown mechanism(s). Methods: Human primary astrocytes were exposed to several HIV proteins as well as to HIV, and expression and function of Connexin43- and Connexin30-containing channels were determined by western blot, immunofluorescence, microinjection of a fluorescent tracer and chromatin immunoprecipitation (ChIP). Results: Here, we demonstrate that HIV infection increases Cx43 expression in vivo. HIV-tat, the transactivator of the virus, and no other HIV proteins tested, increases Cx43 expression and maintains functional gap junctional communication in human astrocytes. Cx43 upregulation is mediated by binding of the HIV-tat protein to the Cx43 promoter, but not to the Cx30 promoter, resulting in increased Cx43 messenger RNA (mRNA) and protein as well as gap junctional communication. Conclusions: We propose that HIV-tat contributes to the spread of intracellular toxic signals generated in a few HIV-infected cells into surrounding uninfected cells by upregulating gap junctional communication. In the current antiretroviral era, where HIV replication is often completely suppressed, viral factors such as HIV-tat are still produced and released from infected cells. Thus, blocking the effects of HIV-tat could result in new strategies to reduce the damaging consequences of HIV infection of the CNS.

Original languageEnglish (US)
Article number54
JournalJournal of Neuroinflammation
Volume13
Issue number1
DOIs
StatePublished - Mar 2 2016
Externally publishedYes

Fingerprint

Human Trafficking
Connexin 43
Astrocytes
HIV
Communication
HIV Infections
Human Immunodeficiency Virus Proteins
Gap Junctions
Up-Regulation
Human Immunodeficiency Virus tat Gene Products
Trans-Activators
Chromatin Immunoprecipitation
Poisons
Microinjections
Virus Diseases
Fluorescent Antibody Technique
Western Blotting

Keywords

  • AIDS
  • Connexin
  • Dementia
  • Gap junctions
  • Glia

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

HIV-tat alters Connexin43 expression and trafficking in human astrocytes : Role in NeuroAIDS. / Berman, Joan W.; Carvallo, Loreto; Buckner, Clarisa M.; Luers, Aimée; Prevedel, Lisa; Bennett, Michael V.; Eugenin, Eliseo.

In: Journal of Neuroinflammation, Vol. 13, No. 1, 54, 02.03.2016.

Research output: Contribution to journalArticle

Berman, Joan W. ; Carvallo, Loreto ; Buckner, Clarisa M. ; Luers, Aimée ; Prevedel, Lisa ; Bennett, Michael V. ; Eugenin, Eliseo. / HIV-tat alters Connexin43 expression and trafficking in human astrocytes : Role in NeuroAIDS. In: Journal of Neuroinflammation. 2016 ; Vol. 13, No. 1.
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AU - Buckner, Clarisa M.

AU - Luers, Aimée

AU - Prevedel, Lisa

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AU - Eugenin, Eliseo

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AB - Background: HIV-associated neurocognitive disorders (HAND) are a major complication in at least half of the infected population despite effective antiretroviral treatment and immune reconstitution. HIV-associated CNS damage is not correlated with active viral replication but instead is associated with mechanisms that regulate inflammation and neuronal compromise. Our data indicate that one of these mechanisms is mediated by gap junction channels and/or hemichannels. Normally, gap junction channels shutdown under inflammatory conditions, including viral diseases. However, HIV infection upregulates Connexin43 (Cx43) expression and maintains gap junctional communication by unknown mechanism(s). Methods: Human primary astrocytes were exposed to several HIV proteins as well as to HIV, and expression and function of Connexin43- and Connexin30-containing channels were determined by western blot, immunofluorescence, microinjection of a fluorescent tracer and chromatin immunoprecipitation (ChIP). Results: Here, we demonstrate that HIV infection increases Cx43 expression in vivo. HIV-tat, the transactivator of the virus, and no other HIV proteins tested, increases Cx43 expression and maintains functional gap junctional communication in human astrocytes. Cx43 upregulation is mediated by binding of the HIV-tat protein to the Cx43 promoter, but not to the Cx30 promoter, resulting in increased Cx43 messenger RNA (mRNA) and protein as well as gap junctional communication. Conclusions: We propose that HIV-tat contributes to the spread of intracellular toxic signals generated in a few HIV-infected cells into surrounding uninfected cells by upregulating gap junctional communication. In the current antiretroviral era, where HIV replication is often completely suppressed, viral factors such as HIV-tat are still produced and released from infected cells. Thus, blocking the effects of HIV-tat could result in new strategies to reduce the damaging consequences of HIV infection of the CNS.

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KW - Connexin

KW - Dementia

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