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 #
5R01AG043384-03
Application #
8662672
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Mackiewicz, Miroslaw
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Var, Susanna R; Day, Tyler R C; Vitomirov, Andrej et al. (2016) Mitochondrial injury and cognitive function in HIV infection and methamphetamine use. AIDS 30:839-48
Soontornniyomkij, Virawudh; Kesby, James P; Morgan, Erin E et al. (2016) Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models. J Neuroimmune Pharmacol 11:495-510
Kim, Changyoun; Lee, He-Jin; Masliah, Eliezer et al. (2016) Non-cell-autonomous Neurotoxicity of α-synuclein Through Microglial Toll-like Receptor 2. Exp Neurobiol 25:113-9
Avdoshina, Valeria; Fields, Jerel Adam; Castellano, Paul et al. (2016) The HIV Protein gp120 Alters Mitochondrial Dynamics in Neurons. Neurotox Res 29:583-93
Fields, Jerel Adam; Serger, Elisabeth; Campos, Sofia et al. (2016) HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders. Neurobiol Dis 86:154-69
Soontornniyomkij, Virawudh; Umlauf, Anya; Soontornniyomkij, Benchawanna et al. (2016) Lifetime methamphetamine dependence is associated with cerebral microgliosis in HIV-1-infected adults. J Neurovirol 22:650-660
Kim, Changyoun; Lv, Guohua; Lee, Jun Sung et al. (2016) Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril. Sci Rep 6:30891
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34
Fields, Jerel A; Overk, Cassia; Adame, Anthony et al. (2016) Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity. J Neuroinflammation 13:120
Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352

Showing the most recent 10 out of 43 publications