HIV-1-Associated Neurocognitive Disorders (HAND) remain prevalent and poorly understood complications of HIV infection, impacting mortality and occurring even in individuals with effective viral suppression by combination antiretroviral therapy (cART). Wide variation in the expression of HAND in HIV-infected individuals implicates host genomic variation in its pathogenesis;the relative contributions of HIV disease progression, neuroinflammation, and the mitochondrial effects of cART are unknown. Abnormal mitochondrial function influences neurodegenerative processes in model systems and is common in human neurocognitive disorders. Regulated iron transport in the central nervous system (CNS), which is incompletely understood, is vital for normal mitochondrial functions like oxidative phosphorylation (OXPHOS) and control of programmed cell death;recent research also reveals intimate links between iron transport and inflammation. Coordinated studies of variants in nuclear DNA (nDNA) and the distinct mitochondrial DNA (mtDNA) genome that influence iron metabolism and mitochondrial OXPHOS may significantly advance understanding of complex neurocognitive disorders such as HAND. Our research team has led efforts to understand the role of variation in both iron-related nDNA genes and mtDNA in cART-associated complications, including peripheral neuropathy, as part of ongoing collaborations with the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Study group. Based on our findings and the literature to date, we hypothesize that nDNA and mtDNA variants that impact iron transport and mitochondrial OXPHOS independently and jointly influence intermediate HAND-associated phenotypes, such as inflammation biomarker levels in CSF, iron transport across the blood-brain barrier as evidenced by levels of iron-related proteins in cerebrospinal fluid (CSF), mtDNA copy number, and genomic DNA methylation patterns, including methylation of inflammation- and iron- related genes. This highly collaborative proposal builds on the multi-disciplinary expertise of several research teams, joint preliminary data, and exceptional CHARTER Study resources. Importantly, it will leverage existing, NIH-funded projects within CHARTER by creating a rich, bi-genomic (nDNA and mtDNA) database linked to blood and cerebrospinal fluid (CSF) biomarker data and to meticulous neurocognitive assessments in 1000 subjects. We will use both state-of-the-art and novel computational approaches to characterize genomic regulation of HAND through three Specific Aims: 1) To determine effects of iron-related nDNA and mtDNA variants on neuroinflammatory biomarker levels in CSF;2) To determine effects of nDNA and mtDNA variants on iron-related protein profiles and mononuclear-cell mtDNA copy number in CSF;and 3) to determine the proportion of HAND susceptibility that is attributable to nDNA (iron-related) and mtDNA genomic regulation of CSF intermediate phenotypes.

Public Health Relevance

The goal of the proposed research is to explore the role of human nuclear (chromosomal) genes and mitochondrial genes that influence iron metabolism and mitochondrial function in the risk of HIV-1-associated neurocognitive disorders (HAND). Results from these studies will improve public health by enhancing our understanding of relationships between these genes and effects of HIV infection and its treatment on the central nervous system, and by informing future clinical trials designed to improve outcomes of HIV-infected persons across the world using personalized approaches to prevent and/or treat HAND. These studies are also relevant for non-HIV-related diseases and the public health of non-HIV-infected populations because nuclear and mitochondrial genes are important in many other conditions affecting the central nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH095621-04
Application #
8658731
Study Section
Special Emphasis Panel (ZMH1-ERB-M (03))
Program Officer
Joseph, Jeymohan
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2014-05-05
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$521,683
Indirect Cost
$153,283
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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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
Crist, Matthew B; Melekhin, Vlada V; Bian, Aihua et al. (2013) Higher serum iron is associated with increased oxidant stress in HIV-infected men. J Acquir Immune Defic Syndr 64:367-73
Nguyen, Anh; Rossi, Steven; Croteau, David et al. (2013) Etravirine in CSF is highly protein bound. J Antimicrob Chemother 68:1161-8
Hulgan, Todd; Gerschenson, Mariana (2012) HIV and mitochondria: more than just drug toxicity. J Infect Dis 205:1769-71