title: Investigating the role of ankyrin-rich membrane spanning protein in human immunodeficiency virus type-1 Tat-induced microglia activation.
abstract: Long-term persistence of human immunodeficiency virus type-1 (HIV) in the central nervous system (CNS) results in mild to severe neurocognitive impairment in a significant proportion of the HIV-infected population. These neurological deficits are known as HIV-associated neurocognitive disorders (HAND). Microglia are CNS-resident immune cells that are directly infected by HIV and consequently secrete proinflammatory molecules that contribute to HIV-induced neuroinflammation. Indeed, the number of activated macrophage and microglia in the brain is more highly correlated with cognitive impairment than the amount of neuronal apoptosis. Ankyrin-rich membrane spanning protein (ARMS/Kidins220) is a multidomain transmembrane protein that is involved with neurotrophin signaling in the CNS. We have previously established the role of ARMS in mediating neuronal survival via a neurotrophin-dependent mechanism. Recent reports also have suggested that ARMS is involved with cell signaling in multiple immune cell types. In this study, we aim to investigate the role of ARMS in HIV Tat-mediated microglial cell activation by employing in vitro methods. Following ARMS depletion by a lentivirus encoding ARMS-specific short hairpin RNA (shRNA), we observed a marked reduction in the HIV Tat-induced proinflammatory response, associated with loss of tumor necrosis factor alpha production and nuclear factor-kappa B (NF-κB) activation. Furthermore, co-immunoprecipitation studies suggested that ARMS physically interacts with inhibitory kappa B kinase subunits in order to facilitate NF-κB activation. Our results establish the role of ARMS in microglial activation by HIV Tat and warrant additional studies to better understand these molecular mechanisms, which may uncover novel therapeutic targets for the treatment of HAND.
authors: Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 672, Rochester, NY, 14642, USA, Vir_Singh@urmc.rochester.edu.
authors: Vir B
authors: VB
authors: Singh
authors: Alicia K
authors: AK
authors: Wooten
authors: Joseph W
authors: JW
authors: Jackson
authors: Sanjay B
authors: SB
authors: Maggirwar
authors: Michelle
authors: M
authors: Kiebala
mesh_terms: D015526:AIDS Dementia Complex / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D015497:HIV-1; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C482591:KIDINS220 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus
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