Dysregulated AB in HAND: The Role of GP120 Induced Endoplasmic Reticulum Stress

Project Summary/Abstract: Human immunodeficiency virus (HIV) infection in the brain may lead to HIV-Associated Neurocognitive Disorder (HAND). HAND is characterized by cognitive, motor, and behavioral impairments and the disorder remains prevalent even in the combination anti-retroviral therapy (cART) era. In HAND, one way that HIV is able to exert its neurotoxic effects in the central nervous system (CNS) is through the actions of viral proteins, such as the envelope glycoprotein gp120 (gp120). Studies have linked HIV infection in the CNS to increased intracellular accumulation of the amyloid beta (Aβ) peptide, and Aβ aggregation may promote neurotoxicity and neuroinflammation. Notably, it is unclear what the mechanisms underlying Aβ accumulation in HAND are. Studies have shown that gp120 may be internalized into neurons and lead to neuronal degeneration, and preliminary data shows that gp120 may induce Aβ. In this project, I will investigate gp120 induced endoplasmic reticulum (ER) stress as a mechanism for increased Aβ accumulation in HAND. I will show that the HIV envelope protein gp120 leads to increased buildup of Aβ, as well as ER stress and ER calcium depletion. I will also show that blocking gp120 from binding to microtubules prevents gp120 from traveling towards ER, disrupting ER function, and inducing Aβ aggregation. Finally, I will investigate whether markers of ER stress may be used as biomarkers in HAND. To do this, I will use a combination of in vivo and in vitro methods, protein quantification methods, and calcium imaging. In addition, I will utilize samples of cerebrospinal fluid (CSF) from people living with HIV and employ mass spectrometry to investigate the correlation between levels of Aβ and gp120, as well as levels of ER stress proteins and gp120. Together, this set of experiments may suggest that gp120 induced disruption of ER homeostasis is associated with Aβ accumulation in the CNS. This research at Georgetown University is important for our current understanding of HAND mechanisms and will provide me with the training necessary to help me achieve my long-term goals as a molecular researcher.