title: HIV-tat alters Connexin43 expression and trafficking in human astrocytes: role in NeuroAIDS.
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.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA. joan.berman@einstein.yu.edu.|Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA. joan.berman@einstein.yu.edu.
authors.forename: Joan W
authors.initials: JW
authors.lastname: Berman
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA. loreto.carvallo-torres@einstein.yu.edu.
authors.forename: Loreto
authors.initials: L
authors.lastname: Carvallo
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA. bucknercm@niaid.nih.gov.|Current address: Laboratory of Immunoregulation, NIAID, Bethesda, MD, USA. bucknercm@niaid.nih.gov.
authors.forename: Clarisa M
authors.initials: CM
authors.lastname: Buckner
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA. aimee.luers@phd.einstein.yu.edu.
authors.forename: Aimée
authors.initials: A
authors.lastname: Luers
authors.affiliation: Public Health Research Institute (PHRI), 225 Warren Street, Newark, NJ, 07103, USA.|Department of Microbiology and Molecular Genetics, Rutgers University, 225 Warren Street, Newark, NJ, 07103, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Prevedel
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA. michael.bennett@einstein.yu.edu.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Bennett
authors.affiliation: Public Health Research Institute (PHRI), 225 Warren Street, Newark, NJ, 07103, USA. eliseo.eugenin@rutgers.edu.|Department of Microbiology and Molecular Genetics, Rutgers University, 225 Warren Street, Newark, NJ, 07103, USA. eliseo.eugenin@rutgers.edu.
authors.forename: Eliseo A
authors.initials: EA
authors.lastname: Eugenin
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000378:metabolism* / Q000473:pathology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D018031:Connexin 43 / Q000096:biosynthesis* / Q000235:genetics; D017629:Gap Junctions / Q000187:drug effects; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D018031:Connexin 43; D034741:RNA, Small Interfering; D054322:tat Gene Products, Human Immunodeficiency Virus