PMID- 26637429 OWN - NLM STAT- MEDLINE DCOM- 20180124 LR - 20210726 IS - 1538-2443 (Electronic) IS - 1355-0284 (Print) IS - 1355-0284 (Linking) VI - 22 IP - 4 DP - 2016 Aug TI - Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV. PG - 431-41 LID - 10.1007/s13365-015-0410-7 [doi] AB - 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-alpha), macrophage inflammatory protein 1-alpha (MIP1-alpha), 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-alpha genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-alpha 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. FAU - Levine, Andrew J AU - Levine AJ AD - Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA. ajlevine@mednet.ucla.edu. FAU - Soontornniyomkij, Virawudh AU - Soontornniyomkij V AD - Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA. FAU - Achim, Cristian L AU - Achim CL AD - Departments of Psychiatry and Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA. FAU - Masliah, Eliezer AU - Masliah E AD - Departments of Neurosciences and Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA. FAU - Gelman, Benjamin B AU - Gelman BB AD - Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA. FAU - Sinsheimer, Janet S AU - Sinsheimer JS AD - Departments of Human Genetics and Biomathematics, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA. FAU - Singer, Elyse J AU - Singer EJ AD - Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA. FAU - Moore, David J AU - Moore DJ AD - Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA. LA - eng GR - U24 MH100929/MH/NIMH NIH HHS/United States GR - R01 MH105319/MH/NIMH NIH HHS/United States GR - U01 MH083500/MH/NIMH NIH HHS/United States GR - U24 MH100928/MH/NIMH NIH HHS/United States GR - R24 MH059745/MH/NIMH NIH HHS/United States GR - R24 NS038841/NS/NINDS NIH HHS/United States GR - R01 MH096648/MH/NIMH NIH HHS/United States GR - N01 MH032002/MH/NIMH NIH HHS/United States GR - P41 RR013642/RR/NCRR NIH HHS/United States GR - P30 MH062512/MH/NIMH NIH HHS/United States GR - U24 MH100930/MH/NIMH NIH HHS/United States GR - R01 GM053275/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20151204 PL - United States TA - J Neurovirol JT - Journal of neurovirology JID - 9508123 RN - 0 (AIF1 protein, human) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Amyloid beta-Peptides) RN - 0 (Biomarkers) RN - 0 (CCL2 protein, human) RN - 0 (Calcium-Binding Proteins) RN - 0 (Chemokine CCL2) RN - 0 (DNA-Binding Proteins) RN - 0 (IL1A protein, human) RN - 0 (Interleukin-1alpha) RN - 0 (MAP2 protein, human) RN - 0 (MAPKAP1 protein, human) RN - 0 (Microfilament Proteins) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Receptors, Dopamine) RN - 0 (SYP protein, human) RN - 0 (Synaptophysin) SB - IM MH - AIDS Dementia Complex/genetics/immunology/*pathology/virology MH - Adaptor Proteins, Signal Transducing/genetics/immunology MH - Adult MH - Amyloid beta-Peptides/genetics/immunology MH - Biomarkers/metabolism MH - Calcium-Binding Proteins MH - Chemokine CCL2/genetics/immunology MH - DNA-Binding Proteins/genetics/immunology MH - Female MH - Frontal Lobe/immunology/pathology/virology MH - Gene Expression MH - Hippocampus/immunology/pathology/virology MH - Humans MH - Interleukin-1alpha/genetics/immunology MH - Male MH - Microfilament Proteins MH - Microtubule-Associated Proteins/*genetics/immunology MH - Middle Aged MH - *Multilevel Analysis MH - Putamen/immunology/pathology/virology MH - Receptors, Dopamine/genetics/immunology MH - Severity of Illness Index MH - Synaptophysin/*genetics/immunology MH - Viral Load MH - *Virus Replication PMC - PMC4893344 MID - NIHMS742920 OTO - NOTNLM OT - HIV OT - HIV-associated neurocognitive disorders OT - Histopathology OT - Host genetic OT - NeuroAIDS OT - Synaptodendritic EDAT- 2015/12/08 06:00 MHDA- 2018/01/25 06:00 PMCR- 2017/08/01 CRDT- 2015/12/06 06:00 PHST- 2015/09/24 00:00 [received] PHST- 2015/11/19 00:00 [accepted] PHST- 2015/11/13 00:00 [revised] PHST- 2015/12/06 06:00 [entrez] PHST- 2015/12/08 06:00 [pubmed] PHST- 2018/01/25 06:00 [medline] PHST- 2017/08/01 00:00 [pmc-release] AID - 10.1007/s13365-015-0410-7 [pii] AID - 10.1007/s13365-015-0410-7 [doi] PST - ppublish SO - J Neurovirol. 2016 Aug;22(4):431-41. doi: 10.1007/s13365-015-0410-7. Epub 2015 Dec 4.