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Antioxidant Sestrin-2 Redistribution to Neuronal Soma in Human Immunodeficiency Virus-Associated Neurocognitive Disorders

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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.

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Acknowledgments

This work was supported in part by the Don & Marilyn Short Fellowship in Parkinson’s Disease (to V. S.) and the United States National Institutes of Health grants R25 MH81482 (to V. S.), P50 DA26306 and R03 DA27513 (to V. S, B. S., and C. L. A.), P30 MH62512 and U01 MH83506 (to C. L. A.), R24 MH59745 (to D. J. M.), and P50 AG16570 and U01 AI35040 (S. T. and H. V. V.). DeltaVision® RT deconvolution microscopy was supported by the University of California, San Diego Neuroscience Microscopy Shared Facility grant P30 NS047101.

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The authors declare that they have no actual or potential conflict of interest.

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Authors and Affiliations

  1. HIV Neurobehavioral Research Program and Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, USA

    Virawudh Soontornniyomkij, Benchawanna Soontornniyomkij, David J. Moore, Ben Gouaux, Igor Grant & Cristian L. Achim

  2. HIV Neurobehavioral Research Program and Departments of Pathology and Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA

    Eliezer Masliah

  3. Department of Pathology and Laboratory Medicine (Neuropathology), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Spencer Tung

  4. Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Harry V. Vinters

  5. Department of Psychiatry, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA

    Virawudh Soontornniyomkij

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  1. Virawudh Soontornniyomkij
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Correspondence to Virawudh Soontornniyomkij.

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Soontornniyomkij, V., Soontornniyomkij, B., Moore, D.J. et al. Antioxidant Sestrin-2 Redistribution to Neuronal Soma in Human Immunodeficiency Virus-Associated Neurocognitive Disorders. J Neuroimmune Pharmacol 7, 579–590 (2012). https://doi.org/10.1007/s11481-012-9357-0

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