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

TitleHIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS.
Publication TypeJournal Article
Year of Publication2016
AuthorsBerman, JW, Carvallo, L, Buckner, CM, Luers, A, Prevedel, L, Bennett, MV, Eugenin, EA
JournalJ Neuroinflammation
Volume13
Issue1
Pagination54
Date Published2016 Mar 02
ISSN1742-2094
KeywordsAIDS-Associated Nephropathy, Astrocytes, Brain, Cell Communication, Cells, Cultured, Chromatin Immunoprecipitation, Connexin 43, External, gap junctions, Humans, RNA, Small Interfering, tat Gene Products, Human Immunodeficiency Virus
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.

DOI10.1186/s12974-016-0510-1
Alternate JournalJ Neuroinflammation
PubMed ID26934876
PubMed Central IDPMC4774036
Grant ListU24 MH100929 / MH / NIMH NIH HHS / United States
MH102113 / MH / NIMH NIH HHS / United States
MH090958 / MH / NIMH NIH HHS / United States
R01 MH096625 / MH / NIMH NIH HHS / United States
MH075679 / MH / NIMH NIH HHS / United States
MH096625 / MH / NIMH NIH HHS / United States
R21 MH102113 / MH / NIMH NIH HHS / United States
R01 MH090958 / MH / NIMH NIH HHS / United States
R01 MH075679 / MH / NIMH NIH HHS / United States