In the current era of combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND), mostly in milder forms, continue to affect the clinical outcome of HIV infection, even in the setting of systemic viral suppression. This revised proposal builds on our recent studies showing increased cerebral beta-amyloid (A) accumulation in the brains of HIV infected persons. We have also shown that cerebral A deposition was predictive of HAND among APOE e4 carriers, after adjusting for each co-morbid factor. Accordingly, the detection of APOE e4 and cerebral A deposition, i.e. decreases in cerebro-spinal fluid (CSF) A42 levels, may be useful in identifying HAND subjects who may benefit from A-targeted therapies. Based on our finding that isocortical p-Tau-immunoreactive neurofibrillary pathology was sparse in HIV subjects, CSF p-Tau measurement may be useful in differentiating HAND from Alzheimer's disease (AD) and other tauopathic disorders in older patients. It is also known that HIV infection and antiretroviral (ARV) treatment, particularly with protease inhibitors (ARV-PI) increase the risk of ischemic stroke, including cerebral small vessel disease (CSVD). Our overarching hypothesis is that cerebral A plaque deposition in HIV-infected patients is associated with defective phagocytotic function of microglia and perivascular clearance. We propose a novel concept that CSVD in the context of HIV/ARV-PI co-morbidity is mediated by oxidative stress- induced premature vascular aging and may be one of the key underpinnings of brain amyloid accumulation (via deficient clearance), and HAND. To test our working hypotheses we have formulated 3 specific aims that will navigate from clinico-pathologic and translational validation to mechanistic interventions. SA#1: Study the association between cerebral A plaques, ApoE4 genotype and HAND. We will use qualitative and semi- quantitative IHC to assess cerebral (perineuronal and perivascular) A plaques and compare them to apolipoprotein E (ApoE), and CSF measurements of A isoforms (-38, -40 and -42), in subjects with or without HAND. We will study the cerebral amyloid burden in 200 HIV+ autopsy cases with information on ART regimens and detailed neuromedical history. SA#2: Examine the association between HIV/ARV-PI co-morbidity and premature vascular aging in the human brain, amyloid accumulation, and HAND. We propose that the HIV/ARV-PI co-morbidity is associated with increased prelamin-A accumulation in vascular smooth muscle cells (VSMC) and premature brain vascular aging. SA#3: Investigate in vitro the effects of ARV-PI on macrophage amyloid phagocytosis and VSMC aging. We propose that exposure of VSMC to HIV and ARV-PI induce oxidative stress, leading to reduction in the Zmpste24 level, increased prelamin-A accumulation, and cellular aging; these pathologic processes may be interrupted by treatments with specific rescue drugs. Our proposal will validate the diagnostic value of amyloid monitoring in clinical specimens in individuals with increased genetic risk and identify potential therapeutic targets implicated in amyloid clearance.