People with HIV/AIDS survive to older ages, but we still do not know if or how HIV-associated neurocognitive disorders (HAND) is exacerbated in the aging brain. We will evaluate the hypotheses that brain inflammation drives an interaction between HAND and brain aging by modifying the ubiquitin proteasome system (UPS). The UPS is the main route of neuronal protein turnover;it is required for normal minute-to-minute physiological changes in synaptic potentiation, learning and memory formation. The UPS plays a key role in preventing the accumulation of misfolded neuronal proteins in pathological neurodegeneration during brain aging. We established that the UPS is abnormal in brain cortex of people with HAND: Immunoproteasomes (IPS) are induced in response to interferons. IPS induction was linked solidly with HIV-associated neurocognitive disorders (HAND). It was relevant pathologically because it was prevalent in subjects with HIV encephalitis (HIVE) and/or replicating HIV concentration in the brain. It was anatomically pervasive in critical neuronal compartments including synapses, axons and neuronal nuclei, perikarya, and isolated synaptosomes. The proposal will test the hypothesis that IPS induction perturbs the synaptic protein economy by diverting the UPS substrate repertoire pathologically, which alters the substrate repertoire, synaptic protein turnover, and synaptic plasticity in HAND and brain aging.
The first aim will use human brain specimens to determine how IPS induction affects macromolecular assembly and enzymatic functions of the UPS, including the dynamic interaction with synaptic proteins.
The second aim will use interferon-stimulated mixed brain cell cultures to determine how IPS induction influences synaptic protein turnover and holoenzyme kinetics, and will determine whether inhibiting the IPS reverses these changes in the synaptic protein economy.
A final aim will use autopsy specimens to determine if the age-of-onset or rate-of-accumulation of misfolded proteins during pathological brain aging is perturbed in association with IPS induction. The program overall addresses a highly novel mechanism for synaptic dysfunction in HAND and has important implications for the mechanism of interaction between pathological brain aging and HIV/AIDS.

Public Health Relevance

The project is important because it will clearly define a novel basic mechanism regarding how HIV infection in the brain disturbs learning and memory, and how HIV worsens brain degeneration during aging. The studies will determine if changes in brain proteins that occur can be blocked, in order to stop dementia and brain aging in HIV infected people

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS072005-05
Application #
8699279
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Galveston
State
TX
Country
United States
Zip Code
77555
Gill, Alexander J; Kovacsics, Colleen E; Cross, Stephanie A et al. (2014) Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders. J Clin Invest 124:4459-72
Vartak-Sharma, Neha; Gelman, Benjamin B; Joshi, Chaitanya et al. (2014) Astrocyte elevated gene-1 is a novel modulator of HIV-1-associated neuroinflammation via regulation of nuclear factor-?B signaling and excitatory amino acid transporter-2 repression. J Biol Chem 289:19599-612
Grant, Igor; Franklin Jr, Donald R; Deutsch, Reena et al. (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82:2055-62
Gill, Alexander J; Kolson, Dennis L (2013) Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy. Crit Rev Immunol 33:307-59
Nguyen, Anh; Rossi, Steven; Croteau, David et al. (2013) Etravirine in CSF is highly protein bound. J Antimicrob Chemother 68:1161-8
Gelman, Benjamin B; Lisinicchia, Joshua G; Morgello, Susan et al. (2013) Neurovirological correlation with HIV-associated neurocognitive disorders and encephalitis in a HAART-era cohort. J Acquir Immune Defic Syndr 62:487-95