The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment

et al. (2012) The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV- Associated Neurocognitive Impairment. PLoS ONE 7(9): e46178. doi:10.1371/journal.pone.0046178 The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment Benjamin B. Gelman 0 Tiansheng Chen 0 Joshua G. Lisinicchia 0 Vicki M. Soukup 0 J. Russ Carmical 0 Jonathan M. Starkey 0 Eliezer Masliah 0 Deborah L. Commins 0 Dianne Brandt 0 Igor Grant 0 Elyse J. Singer 0 Andrew J. Levine 0 Jeremy Miller 0 Jessica M. Winkler 0 Howard S. Fox 0 Genevie`ve Chene, Institut National de la Sante et de la Recherche Medicale, France 0 1 Department of Pathology, University of Texas Medical Branch , Galveston, Texas , United States of America, 2 Department of Neurology, University of Texas Medical Branch , Galveston, Texas , United States of America, 3 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch , Galveston, Texas , United States of America, 4 Department of Internal Medicine, University of Texas Medical Branch , Galveston, Texas , United States of America, 5 Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America, 6 Department of Pathology, University of Southern California, Los Angeles, California, United States of America, 7 EMMES Corporation , Bethesda , Maryland, United States of America, 8 Department of Psychiatry, University of California San Diego, La Jolla, California, United States of America, 9 Department of Neurology, University of California Los Angeles , Los Angeles , California, United States of America, 10 Department of Biostatistics, University of California Los Angeles , Los Angeles , California, United States of America, 11 Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America, 12 Department of Neurology, Mount Sinai Medical Center , New York, New York , United States of America Background: The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiologies of Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders. Methods: Twenty-four human subjects in four groups were examined A) Uninfected controls; B) HIV-1 infected subjects with no substantial neurocognitive impairment (NCI); C) Infected with substantial NCI without HIV encephalitis (HIVE); D) Infected with substantial NCI and HIVE. RNA from neocortex, white matter, and neostriatum was processed with the AffymetrixH array platform. Results: With HIVE the HIV-1 RNA load in brain tissue was three log10 units higher than other groups and over 1,900 gene probes were regulated. Interferon response genes (IFRGs), antigen presentation, complement components and CD163 antigen were strongly upregulated. In frontal neocortex downregulated neuronal pathways strongly dominated in HIVE, including GABA receptors, glutamate signaling, synaptic potentiation, axon guidance, clathrin-mediated endocytosis and 14-3-3 protein. Expression was completely different in neuropsychologically impaired subjects without HIVE. They had low brain HIV-1 loads, weak brain immune responses, lacked neuronally expressed changes in neocortex and exhibited upregulation of endothelial cell type transcripts. HIV-1-infected subjects with normal neuropsychological test results had upregulation of neuronal transcripts involved in synaptic transmission of neostriatal circuits. Interpretation: Two patterns of brain gene expression suggest that more than one pathophysiological process occurs in HIV-1-associated neurocognitive impairment. Expression in HIVE suggests that lowering brain HIV-1 replication might improve NCI, whereas NCI without HIVE may not respond in kind; array results suggest that modulation of transvascular signaling is a potentially promising approach. Striking brain regional differences highlighted the likely importance of circuit level disturbances in HIV/AIDS. In subjects without impairment regulation of genes that drive neostriatal synaptic plasticity reflects adaptation. The array provides an infusion of public resources including brain samples, clinicopathological data and correlative gene expression data for further exploration (http://www.nntc.org/gene-array-project). - Funding: Financial support was provided through the following cooperative agreements from the US National Institutes of Health U01MH083507; U01MH083501; U01MH083500; U01MH083506; U01MH083545. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. One of the five cooperative agreements was with the EMMES Corporation. The EMMES Corporation in cooperation with the United States National Institutes of Health maintains the integrity of databases pertaining to this study, including patient confidentiality and compliance with regulations pertaining to health record information. Competing Interests: One of the authors is employed by the EMMES Corporation. The EMMES Corporation is engaged in a cooperative agreement with the United States National Institutes of Health to manage, insure patient confidentiality, and maintain integrity of databases that pertain to the National NeuroAIDS Tissue Consortium, including the data from this study. This author and the Corporation facilitate the sharing and distribution of NNTC data to the public. Thus, the affiliation does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. All of the remaining authors declare that no competing interests exist. The worldwide pandemic of Human Immunodeficiency Virus type 1 (HIV-1) infection began in the early 1980s. Morbidity and mortality often were due to central nervous system (CNS) pathology caused by CNS HIV-1 infection and opportunistic infections. Neurocognitive impairment (NCI) occurred most often in people with end-stage Acquired Immunodeficiency Syndrome (AIDS). The most severe form of neurocognitive impairment became recognized as the AIDS dementia complex, and later as HIV-associated dementia (HAD). HAD was associated strongly with active HIV-1 replication in the CNS and a neuropathological inflammatory response known as HIV encephalitis (HIVE) [1]. Strategies to pursue the pathophysiology and treatment of HAD focused on HIVE primarily, but up to half of the people with HAD do not exhibit HIVE at autopsy. Conversely, decedents with HIVE often were not demented [2,3,4]. The incidence of progression to end-stage AIDS and severe dementia was reduced after highly active antiretroviral therapy (HAART) was introduced. The prevalence of HIVE in autopsy surveys did not decline as sharply because the population of decedents is skewed to those at the end-stages [5,6,7]. With improved survival mild forms of NCI such as asymptomatic neurocognitive impairment and mild neurocognitive disorder remain (...truncated)