UPREGULATION OF SUPEROXIDE DISMUTASE 2 BY ASTROCYTES IN THE SIV/MACAQUE MODEL OF HIV-ASSOCIATED NEUROLOGIC DISEASE

Sullivan, M. N.; Brill, S. A.; Mangus, L. M.; Jeong, Y. J.; Solis, C. V.; Knight, A. C.; Colantuoni, C.; Keceli, G.; Paolocci, N.; Queen, S. E.; Mankowski, J. L.

doi:10.1101/2020.05.05.078691

bioRxiv · 10.1101/2020.05.05.078691

UPREGULATION OF SUPEROXIDE DISMUTASE 2 BY ASTROCYTES IN THE SIV/MACAQUE MODEL OF HIV-ASSOCIATED NEUROLOGIC DISEASE

Sullivan, M. N.·Brill, S. A.·Mangus, L. M.·Jeong, Y. J.·Solis, C. V.·Knight, A. C.·Colantuoni, C.·Keceli, G.·Paolocci, N.·Queen, S. E.·Mankowski, J. L.

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Abstract

HIV-associated neurocognitive disorders (HAND) remain prevalent despite implementation of antiretroviral therapy (ART). Development of HAND is linked to mitochondrial dysfunction and oxidative stress in the brain; therefore, upregulation of antioxidant defenses is critical to curtail neuronal damage. Superoxide dismutase 2 (SOD2) is a mitochondrial antioxidant enzyme essential for maintaining cellular viability. We hypothesized that SOD2 was upregulated during retroviral infection. Using a simian immunodeficiency virus (SIV)-infected macaque model of HIV, quantitative PCR showed elevated SOD2 mRNA in cortical gray (GM, 7.6-fold for SIV vs. uninfected) and white matter (WM, 77-fold for SIV vs. uninfected) during SIV infection. Further, SOD2 immunostaining was enhanced in GM and WM from SIV-infected animals. Double immunofluorescence labeling illustrated that SOD2 primarily co-localized with astrocyte marker glial fibrillary acidic protein (GFAP) in SIV-infected animals. Interestingly, in ART-treated SIV-infected animals, brain SOD2 RNA levels were similar to uninfected animals. Additionally, using principal component analysis in a transcriptomic approach, SOD2 and GFAP expression separated SIV-infected from uninfected brain tissue. Projection of these data into a HIV dataset revealed similar expression changes, thereby validating the clinical relevance. Together, our findings suggest that novel SOD2-enhancing therapies may delay the onset or reduce severity of HAND seen in ART-treated HIV-infected patients.

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Sullivan, M. N., Brill, S. A., Mangus, L. M., Jeong, Y. J., Solis, C. V., Knight, A. C., Colantuoni, C., Keceli, G., Paolocci, N., Queen, S. E., Mankowski, J. L.. 2020-05-06. UPREGULATION OF SUPEROXIDE DISMUTASE 2 BY ASTROCYTES IN THE SIV/MACAQUE MODEL OF HIV-ASSOCIATED NEUROLOGIC DISEASE. https://doi.org/10.1101/2020.05.05.078691

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