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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-?), macrophage inflammatory protein 1-alpha (MIP1-?), 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-? genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-? 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.

SUBMITTER: Levine AJ

PROVIDER: S-EPMC4893344 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.

Levine Andrew J AJ Soontornniyomkij Virawudh V Achim Cristian L CL Masliah Eliezer E Gelman Benjamin B BB Sinsheimer Janet S JS Singer Elyse J EJ Moore David J DJ

Journal of neurovirology 20151204 4

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), m ...[more]

PMID: 26637429

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Project description:BackgroundNeurocognitive impairment (NCI) remains an important complication in persons infected with human immunodeficiency virus (HIV). Ancestry-related mitochondrial DNA (mtDNA) haplogroups have been associated with outcomes of HIV infection and combination antiretroviral therapy (CART), and with neurodegenerative diseases. We hypothesize that mtDNA haplogroups are associated with NCI in HIV-infected adults and performed a genetic association study in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort.MethodsCHARTER is an observational study of ambulatory HIV-infected adults. Haplogroups were assigned using mtDNA sequence, and principal components were derived from ancestry-informative nuclear DNA variants. Outcomes were cross-sectional global deficit score (GDS) as a continuous measure, GDS impairment (GDS ? 0.50), and HIV-associated neurocognitive disorder (HAND) using international criteria. Multivariable models were adjusted for comorbidity status (incidental vs contributing), current CART, plasma HIV RNA, reading ability, and CD4 cell nadir.ResultsHaplogroups were available from 1027 persons; median age 43 years, median CD4 nadir 178 cells/mm(3), 72% on CART, and 46% with HAND. The 102 (9.9%) persons of genetically determined admixed Hispanic ancestry had more impairment by GDS or HAND than persons of European or African ancestry (P < .001 for all). In multivariate models including persons of admixed Hispanic ancestry, those with haplogroup B had lower GDS (? = -0.34; P = .008) and less GDS impairment (odds ratio = 0.16; 95% confidence interval, .04, .63; P = .009) than other haplogroups. There were no significant haplogroup associations among persons of European or African ancestry.ConclusionsIn these mostly CART-treated persons, mtDNA haplogroup B was associated with less NCI among persons of genetically determined Hispanic ancestry. mtDNA variation may represent an ancestry-specific factor influencing NCI in HIV-infected persons.

Project description:Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive impairment. While the cause remains unclear, recent gene expression studies have identified genes whose transcription is dysregulated in individuals with HIV-association neurocognitive disorder (HAND). However, the methods for interpretation of such data have lagged behind the technical advances allowing the decoding genetic material. Here, we employ systems biology methods novel to the field of NeuroAIDS to further interrogate extant transcriptome data derived from brains of HIV + patients in order to further elucidate the neuropathogenesis of HAND. Additionally, we compare these data to those derived from brains of individuals with Alzheimer's disease (AD) in order to identify common pathways of neuropathogenesis.In Study 1, using data from three brain regions in 6 HIV-seronegative and 15 HIV + cases, we first employed weighted gene co-expression network analysis (WGCNA) to further explore transcriptome networks specific to HAND with HIV-encephalitis (HIVE) and HAND without HIVE. We then used a symptomatic approach, employing standard expression analysis and WGCNA to identify networks associated with neurocognitive impairment (NCI), regardless of HIVE or HAND diagnosis. Finally, we examined the association between the CNS penetration effectiveness (CPE) of antiretroviral regimens and brain transcriptome. In Study 2, we identified common gene networks associated with NCI in both HIV and AD by correlating gene expression with pre-mortem neurocognitive functioning.Study 1: WGCNA largely corroborated findings from standard differential gene expression analyses, but also identified possible meta-networks composed of multiple gene ontology categories and oligodendrocyte dysfunction. Differential expression analysis identified hub genes highly correlated with NCI, including genes implicated in gliosis, inflammation, and dopaminergic tone. Enrichment analysis identified gene ontology categories that varied across the three brain regions, the most notable being downregulation of genes involved in mitochondrial functioning. Finally, WGCNA identified dysregulated networks associated with NCI, including oligodendrocyte and mitochondrial functioning. Study 2: Common gene networks dysregulated in relation to NCI in AD and HIV included mitochondrial genes, whereas upregulation of various cancer-related genes was found.While under-powered, this study identified possible biologically-relevant networks correlated with NCI in HIV, and common networks shared with AD, opening new avenues for inquiry in the investigation of HAND neuropathogenesis. These results suggest that further interrogation of existing transcriptome data using systems biology methods can yield important information.

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Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.

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Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.

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