Cargando…

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

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 wi...

Descripción completa

Detalles Bibliográficos
Autores principales: Berman, Joan W., Carvallo, Loreto, Buckner, Clarisa M., Luers, Aimée, Prevedel, Lisa, Bennett, Michael V., Eugenin, Eliseo A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774036/
https://www.ncbi.nlm.nih.gov/pubmed/26934876
http://dx.doi.org/10.1186/s12974-016-0510-1
_version_ 1782418844939190272
author Berman, Joan W.
Carvallo, Loreto
Buckner, Clarisa M.
Luers, Aimée
Prevedel, Lisa
Bennett, Michael V.
Eugenin, Eliseo A.
author_facet Berman, Joan W.
Carvallo, Loreto
Buckner, Clarisa M.
Luers, Aimée
Prevedel, Lisa
Bennett, Michael V.
Eugenin, Eliseo A.
author_sort Berman, Joan W.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4774036
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-47740362016-03-03 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 A. J Neuroinflammation Research 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. BioMed Central 2016-03-02 /pmc/articles/PMC4774036/ /pubmed/26934876 http://dx.doi.org/10.1186/s12974-016-0510-1 Text en © Berman et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Berman, Joan W.
Carvallo, Loreto
Buckner, Clarisa M.
Luers, Aimée
Prevedel, Lisa
Bennett, Michael V.
Eugenin, Eliseo A.
HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS
title HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS
title_full HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS
title_fullStr HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS
title_full_unstemmed HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS
title_short HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS
title_sort hiv-tat alters connexin43 expression and trafficking in human astrocytes: role in neuroaids
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774036/
https://www.ncbi.nlm.nih.gov/pubmed/26934876
http://dx.doi.org/10.1186/s12974-016-0510-1
work_keys_str_mv AT bermanjoanw hivtataltersconnexin43expressionandtraffickinginhumanastrocytesroleinneuroaids
AT carvalloloreto hivtataltersconnexin43expressionandtraffickinginhumanastrocytesroleinneuroaids
AT bucknerclarisam hivtataltersconnexin43expressionandtraffickinginhumanastrocytesroleinneuroaids
AT luersaimee hivtataltersconnexin43expressionandtraffickinginhumanastrocytesroleinneuroaids
AT prevedellisa hivtataltersconnexin43expressionandtraffickinginhumanastrocytesroleinneuroaids
AT bennettmichaelv hivtataltersconnexin43expressionandtraffickinginhumanastrocytesroleinneuroaids
AT eugenineliseoa hivtataltersconnexin43expressionandtraffickinginhumanastrocytesroleinneuroaids