Currently over 30 million people live with HIV worldwide. In the US, the aging population represents one of the fastest growing groups with HIV. The Center for Disease Control estimates that by the year 2015, half of all Americans living with HIV will be over the age of 50. The mechanisms of neurodegeneration in aged individuals are not completely understood, however HIV activates apoptotic pathways, dysregulates calcium homeostasis and promotes oxidative stress. Moreover, recent studies have shown that HIV proteins might interfere with clearance pathways such as autophagy, a pathway necessary for protein quality control and elimination of defective older intracellular organelles. Deficits i autophagy have been described in Alzheimer's Disease (AD), Parkinson's Disease (PD) and other aging-related disorders, similarly, neurodegeneration has been linked to defects in autophagy in patients with HIV. We have recently shown that abnormal functioning of the autophagy pathway is associated with progressive accumulation of Amyloid-beta (A?), ?-synuclein (?-syn) and Tau in the CNS of aged HIV human cases and in transgenic (tg) mice expressing HIV-gp120 protein (GFAP-gp120 tg). In this context our hypothesis is that HIV proteins such as Nef might interfere with autophagy by interacting with components of the autophagocytic pathway such as Beclin1. In aged patients with chronic HIV infection, this might result in reduced clearance of neurotoxic proteins and neurodegeneration. The main objectives of this proposal will be to a) better understand the mechanisms through which HIV proteins interfere with autophagy leading to protein accumulation and neurotoxicity, and b) to determine whether activation of the autophagy pathway is neuroprotective in preclinical models of HIV neurotoxicity and aging. For this purpose we propose the following Aims:
Aim 1 : To analyze interactions between HIV proteins and components of the autophagy pathway in brains of aged patients with chronic HIV infection.
Aim 2 : To investigate the role of HIV proteins in the cellular mechanisms of autophagy dysfunction and neurotoxicity.
Aim 3. To determine whether autophagy activation in vivo ameliorates neurodegenerative and behavioral deficits in aged transgenic rodent models of HIV neurotoxicity. This project has the potential to further elucidate the role of autophagy as key downstream mediator of HIV-protein neurotoxicity during aging, which could lead to the development of new therapies and models of HIV-associated neurodegeneration and neuroprotection. Since alterations in autophagy are also present in AD and PD, this project may have broader applications for therapeutic advancements in other age-related neurodegenerative disorders.

Public Health Relevance

In the US, the aging population represents one of the fastest growing groups with HIV however the mechanisms underlying neurodegeneration in aged HIV individuals remain unclear. Recent studies have shown that HIV proteins might interfere with autophagy, a pathway necessary for protein quality control. For this project we propose to better understand the mechanisms through which HIV proteins interfere with autophagy leading to protein accumulation and neurotoxicity, and to determine whether activation of the autophagy pathway is neuroprotective in preclinical models of HIV neurotoxicity and aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG043384-01
Application #
8330095
Study Section
Special Emphasis Panel (ZMH1-ERB-M (02))
Program Officer
Mackiewicz, Miroslaw
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$387,292
Indirect Cost
$137,292
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Valera, Elvira; Masliah, Eliezer (2018) The neuropathology of multiple system atrophy and its therapeutic implications. Auton Neurosci 211:1-6
Fields, Jerel Adam; Spencer, Brian; Swinton, Mary et al. (2018) Alterations in brain TREM2 and Amyloid-? levels are associated with neurocognitive impairment in HIV-infected persons on antiretroviral therapy. J Neurochem 147:784-802
Valera, Elvira; Spencer, Brian; Mott, Jennifer et al. (2017) MicroRNA-101 Modulates Autophagy and Oligodendroglial Alpha-Synuclein Accumulation in Multiple System Atrophy. Front Mol Neurosci 10:329
Fields, Jerel A; Metcalf, Jeff; Overk, Cassia et al. (2017) The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration. J Neurovirol 23:290-303
Valera, Elvira; Spencer, Brian; Fields, Jerel A et al. (2017) Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy. Acta Neuropathol Commun 5:2
Cronin, Peter; McCarthy, Michael J; Lim, Andrew S P et al. (2017) Circadian alterations during early stages of Alzheimer's disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimers Dement 13:689-700
Avdoshina, Valeria; Fields, Jerel Adam; Castellano, Paul et al. (2016) The HIV Protein gp120 Alters Mitochondrial Dynamics in Neurons. Neurotox Res 29:583-593
Spencer, Brian; Desplats, Paula A; Overk, Cassia R et al. (2016) Reducing Endogenous ?-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. J Neurosci 36:7971-84
Spencer, Brian; Kim, Changyoun; Gonzalez, Tania et al. (2016) ?-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease. Hum Mol Genet 25:1100-15
Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352

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