title: Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.
abstract: The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) remains puzzling. We interrogated several levels of data (host genetic, histopathology, brain viral load, and neurocognitive) to identify histopathological changes most relevant to HAND. The design of the study is a clinicopathological study employing genetic association analyses. Data and brain tissue from 80 HIV-infected adults were used. Markers in monocyte chemoattractant protein-1 (MCP-1), interleukin 1-alpha (IL1-α), macrophage inflammatory protein 1-alpha (MIP1-α), DRD3, DRD2, and apolipoprotein E (ApoE) were genotyped. Microtubule associated protein 2 (MAP2), synaptophysin (SYP), human leukocyte antigen-DR (HLA-DR), glial fibrillary acidic protein (GFAP), amyloid beta (A-Beta), and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactivity were quantified in the frontal cortex, putamen, and hippocampus. A composite score for each marker (mean of the three brain regions) was used. Neurocognitive functioning and other clinical variables were determined within 1 year of death. Brain HIV RNA viral load was available for a subset of cases. MAP2 and SYP proved most relevant to neurocognitive functioning. Immunoreactivity of these markers, as well as A-Beta and Iba-1, was correlated with brain HIV RNA viral load. Several genetic markers in combination with other factors predicted histopathology: HIV blood viral load, MIP1-α genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-α genotype predicted GFAP immunoreactivity; ApoE genotype and age at death predicted A-Beta immunoreactivity. These data indicate that HIV replication in the brain is the primary driving force leading to neuroinflammation and dysfunctional protein clearance, as reflected by A-Beta and Iba-1. Downstream to these changes are synaptodendritic degeneration, which is the immediate histopathological substrate of the neurocognitive impairment characteristic of HAND. These intermediate histopathological phenotypes are influenced by host genetic polymorphisms in genes encoding cytokines/chemokines, neuronal protein clearance pathways, and dopaminergic factors.
authors.affiliation: Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA. ajlevine@mednet.ucla.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: Virawudh
authors.initials: V
authors.lastname: Soontornniyomkij
authors.affiliation: Departments of Psychiatry and Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: Cristian L
authors.initials: CL
authors.lastname: Achim
authors.affiliation: Departments of Neurosciences and Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.affiliation: Departments of Human Genetics and Biomathematics, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.affiliation: Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Elyse J
authors.initials: EJ
authors.lastname: Singer
authors.affiliation: Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000821:virology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000328:Adult; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D005625:Frontal Lobe / Q000276:immunology / Q000473:pathology / Q000821:virology; D015870:Gene Expression; D006624:Hippocampus / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology; D008297:Male; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D055361:Multilevel Analysis; D011699:Putamen / Q000276:immunology / Q000473:pathology / Q000821:virology; D011954:Receptors, Dopamine / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D016708:Synaptophysin / Q000235:genetics* / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication
chemical_list: C112986:AIF1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D015415:Biomarkers; C111835:CCL2 protein, human; D002135:Calcium-Binding Proteins; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; C508584:IL1A protein, human; D053582:Interleukin-1alpha; C489788:MAP2 protein, human; C493277:MAPKAP1 protein, human; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D011954:Receptors, Dopamine; C569014:SYP protein, human; D016708:Synaptophysin
keywords: HIV; HIV-associated neurocognitive disorders; Histopathology; Host genetic; NeuroAIDS; Synaptodendritic