title: Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder.
abstract: BACKGROUND
  HIV-associated neurocognitive disorder (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occurs in approximately 50% of HIV infected individuals. In the United States, the prevalence of cigarette smoking ranges from 35-70% in HIV-infected individuals compared to 20% in general population. Cognitive impairment in heavy cigarette smokers has been well reported. However, the synergistic effects of nicotine and HIV infection and the underlying mechanisms in the development of HAND are unknown.
  
  
  RESULTS
  In this study, we explored the role of nicotine in the progression of HAND using SK-N-MC, a neuronal cell line. SK-N-MC cells were infected with HIV-1 in the presence or absence of nicotine for 7 days. We observed significant increase in HIV infectivity in SK-N-MC treated with nicotine compared to untreated HIV-infected neuronal cells. HIV and nicotine synergize to significantly dysregulate the expression of synaptic plasticity genes and spine density; with a concomitant increase of HDAC2 levels in SK-N-MC cells. In addition, inhibition of HDAC2 up-regulation with the use of vorinostat resulted in HIV latency breakdown and recovery of synaptic plasticity genes expression and spine density in nicotine/HIV alone and in co-treated SK-N-MC cells. Furthermore, increased eIF2 alpha phosphorylation, which negatively regulates eukaryotic translational process, was observed in HIV alone and in co-treatment with nicotine compared to untreated control and nicotine alone treated SK-N-MC cells.
  
  
  CONCLUSIONS
  These results suggest that nicotine and HIV synergize to negatively regulate the synaptic plasticity gene expression and spine density and this may contribute to the increased risk of HAND in HIV infected smokers. Apart from disrupting latency, vorinostat may be a useful therapeutic to inhibit the negative regulatory effects on synaptic plasticity in HIV infected nicotine abusers.
authors.forename: Venkata Subba Rao
authors.initials: VS
authors.lastname: Atluri
authors.forename: Sudheesh
authors.initials: S
authors.lastname: Pilakka-Kanthikeel
authors.forename: Thangavel
authors.initials: T
authors.lastname: Samikkannu
authors.forename: Vidya
authors.initials: V
authors.lastname: Sagar
authors.forename: Kesava Rao Venkata
authors.initials: KR
authors.lastname: Kurapati
authors.forename: Shailendra K
authors.initials: SK
authors.lastname: Saxena
authors.forename: Adriana
authors.initials: A
authors.lastname: Yndart
authors.forename: Andrea
authors.initials: A
authors.lastname: Raymond
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Oscar
authors.initials: O
authors.lastname: Hernandez
authors.affiliation: Department of Immunology, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL -33199, USA. nairm@fiu.edu.
authors.forename: Madhavan P N
authors.initials: MP
authors.lastname: Nair
mesh_terms: D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D049229:Dendritic Spines / Q000187:drug effects / Q000235:genetics*; D018450:Disease Progression; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008954:Models, Biological; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D009538:Nicotine / Q000009:adverse effects*; D010766:Phosphorylation / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D015852:Eukaryotic Initiation Factor-2; D006877:Hydroxamic Acids; D000077337:Vorinostat; D009538:Nicotine; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2