Combination antiretroviral therapy prevents SIV-induced aging in the hippocampus and neurodegeneration throughout the brain.

Virus-induced accelerated aging has been proposed as a potential mechanism underlying the persistence of HIV-associated brain injury (HABI) despite advances in access and adherence to combination antiretroviral therapies (cART). While some studies have demonstrated evidence of accelerated aging in PLWH, studies examining the effects of cART intervention are limited, with most studies being in vitro or utilizing small animal models. Here, we utilized archival FFPE tissues from Simian immunodeficiency virus (SIV) infected rhesus macaques to assess the levels of two proteins commonly associated with aging - the cellular senescence marker p16INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Our central hypothesis was that SIV infection induces accelerated aging phenotypes in the brain characterized by increased expression of p16 and SIRT1 that correlate with increased neurodegeneration, and that cART inhibits this process. We found that SIV infection induced increased GFAP, p16, SIRT1, and neurodegeneration in multiple brain regions. Importantly, cART reduced SIV-induced accelerated aging (p16 and SIRT1) in the hippocampus and neurodegeneration and GFAP expression in the frontal lobe. Combined, these data suggest that cART is both safe and effective in reducing neuroinflammation and age-associated alterations in astrocytes that contribute to neurodegeneration, providing possible therapeutic targets in the treatment of HABI.