This research exploits natural features of the herpesvirus transport protein US9 as a novel approach to study, and possibly modulate, lipid rafts dependent cellular processes relevant to HIV Associated Neurocognitive Disorders (HAND). As lipid rafts represent dynamic platforms for key molecular events likely involved in these conditions, our studies will capitalize on US9 properties to trace HIV-induced changes in lipid rafts, and alter Amyloid Precursor Protein (APP) processing - for both mechanistic and interventional purposes. The proposed experiments will test the hypothesis that HIV-1 gp120/tat favor transport of amyloidogenic enzymes to membrane microdomains, leading to neurotoxicity, and that these viral proteins do not affect intraneuronal distribution of US9. This work will generate a new and powerful strategy capable of studying directly the link between HIV-1 proteins induced changes of lipid rafts and amyloidogenesis, as well as possibly discovering a novel therapeutic approach to decreasing neuronal dysfunction. Briefly, we will use US9 as a molecular tracer of neuronal protein transport to study alterations induced by HIV-1 gp120 and tat in the intraneuronal distribution of lipid rafts-associated proteins that are involved in neurotoxiciy - including, but not limited to, APP processing enzymes (Aim 1). Moreover, through US9-mediated targeting of engineered enzymes altering APP processing, we will increase expression of cellular enzymes that shift APP processing toward the non-amyloidogenic pathway and test the neurotoxic effects of the HIV proteins under these conditions (Aim 2). In order to determine both in vitro and in vivo effects of the viral proteins, these aims include experiments in primary neuronal cultures and small animal models. If successful, this research will help delineate the role of lipid rafts changes in HIV-induced neuronal damage, determine the link between amyloidogenesis and neuronal survival/injury, and lead to potential applications intended to reduce local accumulation of noxious proteins at advanced stages of disease. Thus, both the technical approach and scope of this research are highly innovative and significant, and expected to exert a substantial impact on the field of HAND.
Despite the efficacy of anti-retroviral therapy in controlling peripheral infection and improving life of HIV patients, HIV-associated neurocognitive disorders (HAND) still represent a significant health problem. Due to the longer life expectancy of treated patients, HAND prevalence has markedly increased and it is exacerbated by various comorbid factors, such as drug abuse. Evidence also suggests that HIV may accelerate aging of the CNS. This work will generate a new strategy to directly investigate specific mechanisms of neurotoxicity implicated in both the aging process and HAND (namely alterations of lipid rafts and amyloidogenesis), and will help discovering novel therapeutic approaches for their treatment.
| Brandimarti, Renato; Hill, Gordon S; Geiger, Jonathan D et al. (2017) The lipid raft-dwelling protein US9 can be manipulated to target APP compartmentalization, APP processing, and neurodegenerative disease pathogenesis. Sci Rep 7:15103 |
| Geiger, Jonathan D; Chen, Xuesong (2017) Human Immunodeficiency Virus Transactivator of Transcription-Induced Increases in Depression-like Effects Are Linked to Oxidative Stress. Biol Psychiatry Cogn Neurosci Neuroimaging 2:552-553 |
