Abstract Human immunodeficiency virus (HIV) does not infect neurons, yet dendritic simplification and loss of synapses are still seen in a subset of people living with HIV, despite antiretroviral therapies. HIV can also cause neurocognitive, motor, and behavioral impairments, a constellation of clinical signs grouped under a disease termed HIV-associated neurocognitive disorder (HAND). Nevertheless, the underlying causes of the pathological alterations observed in these individuals are poorly comprehended. Viral proteins, including the envelope protein gp120, have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. Experimental evidence has shown that gp120 is endocytosed into neurons and is transported within the axon to the endoplasmic reticulum (ER) where it causes a dysfunction of endoproteases such as furin, among others. Furin is crucial for the processing of pro-brain-derived neurotrophic factor (BDNF) to mature BDNF. proBDNF activates the neurotrophin receptor p75 (p75NTR), which has been shown to promote the loss of synapses. In the previous grant cycle, we have shown that the removal of one allele of p75NTR rescues the loss of dendritic synapses seen in gp120 transgenic mice. Therefore, we hypothesize that HIV, through gp120, damages p75NTR positive synapses, thus driving synapto-dendritic degeneration observed in HAND. However, the molecular and cellular mechanisms of how gp120, through p75NTR, damages synapses remain under investigation. This application proposes a comprehensive set of experiments to test the main hypothesis. In particular (Aim 1), we will utilize gp120 transgenic mice crossed with p75NTR-/- mice to investigate the molecular mechanisms whereby activation of p75NTR by gp120-induced proBDNF leads to neuronal degeneration. Because p75NTR plays a role in amyloid beta (Ab) processing, we will test the hypothesis that the loss of synapses in HAND is due to Ab accumulation. In Aim 2, we will confirm that gp120 impairs the function of the ER by carrying out a comprehensive analysis of ER stress in both gp120 transgenic mice and cortical neuronal cultures. In Aim 3, we will use HIV negative and HIV positive human samples, including the cerebrospinal fluid (CSF), to establish whether the presence of gp120 in human brains correlates with the degree of neurocognitive impairments. We will determine the levels of gp120, markers of neuronal damage (e.g. microtubule associated protein-2), inflammation, and levels of Ab in different subgroups of HAND subjects. Particular attention will be paid to HAND subjects with APOE alleles that are considered neuroprotective (e.g. e2) or risk factors (e4). We expect to provide new significant data on the role of p75NTR in HIV-mediated synaptic simplification. Knowledge into the diverse role of p75NTR in HAND and other neurodegenerative diseases is likely to provide a better understanding of these diseases and elucidate primary and adjuvant p7...