title: HIV-1 Tat upregulates expression of histone deacetylase-2 (HDAC2) in human neurons: implication for HIV-associated neurocognitive disorder (HAND).
abstract: Histone deacetylases (HDACs) play a pivotal role in epigenetic regulation of transcription and homeostasis of protein acetylation in histones and other proteins involved in chromatin remodeling. Histone hypoacetylation and transcriptional dysfunction have been shown to be associated with a variety of neurodegenerative diseases. More recently, neuron specific overexpression of HDAC2 has been shown to modulate synaptic plasticity and learning behavior in mice. However, the role of HDAC2 in development of HIV-associated neurocognitive disorders (HAND) is not reported. Herein we report that HIV-1 Tat protein upregulate HDAC2 expression in neuronal cells leading to transcriptional repression of genes involved in synaptic plasticity and neuronal function thereby contributing to the progression of HAND. Our results indicate upregulation of HDAC2 by Tat treatment in dose and time dependant manner by human neuroblastoma SK-N-MC cells and primary human neurons. Further, HDAC2 overexpression was associated with concomitant downregulation in CREB and CaMKIIa genes that are known to regulate neuronal activity. These observed effects were completely blocked by HDAC2 inhibition. These results for the first time suggest the possible role of HDAC2 in development of HAND. Therefore, use of HDAC2 specific inhibitor in combination with HAART may be of therapeutic value in treatment of neurocognitive disorders observed in HIV-1 infected individuals.
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA.
authors.forename: Zainulabedin M
authors.initials: ZM
authors.lastname: Saiyed
authors.forename: Nimisha
authors.initials: N
authors.lastname: Gandhi
authors.forename: Marisela
authors.initials: M
authors.lastname: Agudelo
authors.forename: Jessica
authors.initials: J
authors.lastname: Napuri
authors.forename: Thangavel
authors.initials: T
authors.lastname: Samikkannu
authors.forename: Pichili V B
authors.initials: PV
authors.lastname: Reddy
authors.forename: Pradnya
authors.initials: P
authors.lastname: Khatavkar
authors.forename: Adriana
authors.initials: A
authors.lastname: Yndart
authors.forename: Shailendra K
authors.initials: SK
authors.lastname: Saxena
authors.forename: Madhavan P N
authors.initials: MP
authors.lastname: Nair
mesh_terms: D015526:AIDS Dementia Complex / Q000201:enzymology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000502:physiology*; D015497:HIV-1 / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009474:Neurons / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D015696:Gene Products, tat; D006877:Hydroxamic Acids; C012589:trichostatin A; D056464:Histone Deacetylase 2