title: Antioxidant sestrin-2 redistribution to neuronal soma in human immunodeficiency virus-associated neurocognitive disorders.
abstract: Sestrin-2 is involved in p53-dependent antioxidant defenses and in the maintenance of metabolic homeostasis. We hypothesize that sestrin-2 expression is altered in the brains of subjects diagnosed with human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) due to neuronal oxidative stress. We studied sestrin-2 immunoreactivity in 42 isocortex sections from HIV-1-infected subjects compared to 18 age-matched non-HIV controls and 19 advanced Alzheimer's disease (AD) cases. With HIV infection, the sestrin-2 immunoreactivity pattern shifted from neuropil predominance (N) to neuropil and neuronal-soma co-dominance (NS) and neuronal-soma predominance (S; P < 0.0001, Chi-square test for linear trend). Among HIV cases showing the NS or S pattern, HAND cases were preferentially associated with the S pattern (n = 10 of 20) compared to cognitively intact cases (n = 1 of 11; P = 0.047, Fisher's exact test). In AD brains, sestrin-2 immunoreactivity was mostly intense in the neuropil and co-localized with phospho-Tau immunoreactivity in a subset of neurofibrillary lesions. Phospho-Tau-immunoreactive neurofibrillary lesions were rare in HIV cases and their occurrence was not associated with HAND. Levels of isocortical 8-hydroxy-deoxyguanosine (marker of nucleic acid oxidation) immunoreactivity were not significantly altered in HAND cases compared to cognitively intact HIV cases. In conclusion, the sestrin-2 immunoreactivity redistribution to neuronal soma in HAND suggests unique involvement of sestrin-2 in the pathophysiology of HAND, which is different from the role of sestrin-2 in AD pathogenesis. Alternatively, the difference in sestrin-2 immunoreactivity distribution between HAND and AD may be related to different degrees of severity or stages of oxidative stress.
authors.affiliation: HIV Neurobehavioral Research Program and Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, USA. vsoontor@ucsd.edu
authors.forename: Virawudh
authors.initials: V
authors.lastname: Soontornniyomkij
authors.forename: Benchawanna
authors.initials: B
authors.lastname: Soontornniyomkij
authors.forename: David J
authors.initials: DJ
authors.lastname: Moore
authors.forename: Ben
authors.initials: B
authors.lastname: Gouaux
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Spencer
authors.initials: S
authors.lastname: Tung
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
authors.forename: Cristian L
authors.initials: CL
authors.lastname: Achim
mesh_terms: D015526:AIDS Dementia Complex / Q000453:epidemiology / Q000378:metabolism / Q000821:virology; D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000821:virology; D003072:Cognition Disorders / Q000453:epidemiology / Q000378:metabolism* / Q000821:virology; D005260:Female; D015658:HIV Infections / Q000453:epidemiology / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000821:virology; D009687:Nuclear Proteins / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D000975:Antioxidants; D009687:Nuclear Proteins; C465398:SESN2 protein, human; D000084622:Sestrins