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.
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.
|Smieszek, S; Jia, P; Samuels, D C et al. (2018) Nuclear-Mitochondrial interactions influence susceptibility to HIV-associated neurocognitive impairment. Mitochondrion :|
|Jia, Peilin; Zhao, Zhongming; Hulgan, Todd et al. (2017) Genome-wide association study of HIV-associated neurocognitive disorder (HAND): A CHARTER group study. Am J Med Genet B Neuropsychiatr Genet 174:413-426|
|Patton, Stephanie M; Wang, Quan; Hulgan, Todd et al. (2017) Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults. Fluids Barriers CNS 14:11|
|Obermeit, Lisa C; Beltran, Jessica; Casaletto, Kaitlin B et al. (2017) Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining ""symptomatic"" versus ""asymptomatic"" HAND. J Neurovirol 23:67-78|
|Mehta, Sanjay R; Pérez-Santiago, Josué; Hulgan, Todd et al. (2017) Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment. J Neuroinflammation 14:72|
|Samuels, David C; Kallianpur, Asha R; Ellis, Ronald J et al. (2016) European Mitochondrial DNA Haplogroups are Associated with Cerebrospinal Fluid Biomarkers of Inflammation in HIV Infection. Pathog Immun 1:330-351|
|Kallianpur, Asha R; Wang, Quan; Jia, Peilin et al. (2016) Anemia and Red Blood Cell Indices Predict HIV-Associated Neurocognitive Impairment in the Highly Active Antiretroviral Therapy Era. J Infect Dis 213:1065-73|
|Malvar, Jemily; Vaida, Florin; Sanders, Chelsea Fitzsimons et al. (2015) Predictors of new-onset distal neuropathic pain in HIV-infected individuals in the era of combination antiretroviral therapy. Pain 156:731-9|
|Wang, Quan; Yu, Hui; Zhao, Zhongming et al. (2015) EW_dmGWAS: edge-weighted dense module search for genome-wide association studies and gene expression profiles. Bioinformatics 31:2591-4|
|Hulgan, Todd; Samuels, David C; Bush, William et al. (2015) Mitochondrial DNA Haplogroups and Neurocognitive Impairment During HIV Infection. Clin Infect Dis 61:1476-84|
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