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bioRxiv · 10.64898/2025.12.15.694426

Neuroinvasion by Simian Immunodeficiency Virus Triggers Glial Senescence and Accelerated Neurodegeneration

Horn, M. D.·Midkiff, C.·Van Zandt, A. R.·Saied, A. A.·MacLean, A.
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Abstract

Virus-induced accelerated aging has emerged as a potential contributor to HIV-associated neurocognitive disorders (HAND), despite widespread implementation of combination antiretroviral therapy (cART). Although evidence of accelerated aging in people living with HIV (PLWH) has been reported, most investigations of acute infection rely on in vitro systems or small animal models, leaving a critical gap in understanding early neuropathological events. To address this, we analyzed formalin-fixed, paraffin-embedded (FFPE) brain tissues from rhesus macaques acutely infected with simian immunodeficiency virus (SIV). We focused on two key aging-related proteins: the cellular senescence marker p16INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). We hypothesized that accelerated aging phenotypes would be detectable during acute infection, manifesting as increased p16 expression and altered SIRT1 levels, correlating with neurodegeneration. Consistent with this hypothesis, we observed marked upregulation of GFAP and p16, along with evidence of neurodegeneration, across multiple brain regions - including the frontal lobe, caudate, putamen, thalamus, hippocampus, and cerebellum - by 21 days post-infection. These findings suggest that aging-related and senescence pathways are activated almost immediately following HIV infection, highlighting the potential importance of astrocyte- or CNS-specific therapeutic strategies to mitigate early neuropathology.

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Horn, M. D., Midkiff, C., Van Zandt, A. R., Saied, A. A., MacLean, A.. 2025-12-16. Neuroinvasion by Simian Immunodeficiency Virus Triggers Glial Senescence and Accelerated Neurodegeneration. https://doi.org/10.64898/2025.12.15.694426

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