HIV-associated motor neuron disease

Bowen, Lauren N.; Tyagi, Richa; Li, Wenxue; Alfahad, Tariq; Smith, Bryan; Wright, Mary E.; Singer, Elyse J.; Nath, Avindra

doi:10.1212/wnl.0000000000003258

Cited by 69 publications

(39 citation statements)

References 30 publications

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“…Antiretroviral therapy can reverse the symptoms of this ALS-like syndrome in HIV-infected individuals ( Moulignier et al, 2001 ; von Giesen et al, 2002 ), suggesting that HIV replication in the CNS can drive a pathology which symptomatically resembles ALS. Indeed, recent attempts treat HIV-associated motor neuron disease with antiretroviral therapy showed promise, with reversal of recent onset symptoms or a protracted course of the illness following treatment ( Bowen et al, 2016 ). In these patients, the clinical improvement paralleled a decrease in HERV-K viral load in plasma ( Bowen et al, 2016 ).…”

Section: Future Directionsmentioning

confidence: 99%

“…Indeed, recent attempts treat HIV-associated motor neuron disease with antiretroviral therapy showed promise, with reversal of recent onset symptoms or a protracted course of the illness following treatment ( Bowen et al, 2016 ). In these patients, the clinical improvement paralleled a decrease in HERV-K viral load in plasma ( Bowen et al, 2016 ). Future research into HIV-associated motor deficits in pediatric and adult populations should consider the potential of HERV-K in driving motor impairment.…”

Section: Future Directionsmentioning

confidence: 99%

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Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

Douville

Nath

2017

Front. Microbiol.

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Despite the repetitive association of endogenous retroviruses in human disease, the mechanisms behind their pathological contributions remain to be resolved. Here we discuss how neuronal human endogenous retrovirus-K (HERV-K) expression in human immunodeficiency virus (HIV)-infected individuals is a distinct pathological aspect of HIV-associated neurological conditions, such as HIV encephalitis and HIV-associated neurocognitive disorders. Enhanced neuronal HERV-K levels were observed in the majority of HIV-infected individuals, and to a higher degree in brain tissue marked by HIV replication. Moreover, we highlight an important neuropathological overlap between amyotrophic lateral sclerosis and HIV encephalitis, that being the formation of neurotoxic TDP-43 deposits in neurons. Herein, we argue for enhanced transdisciplinary research in the field of ERV biology, using an example of how HERV-K expression has novel mechanistic and therapeutic implications for HIV neuropathology.

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Section: Future Directionsmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

Douville

Nath

2017

Front. Microbiol.

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“…The positive selection of persistent ERVs in the genome may have resulted from increasing the probability of survival to reproductive age [via adaptive effects on placentation (Simpson et al, 1996 ); and immune (Hurst and Magiorkinis, 2015 ) and brain development (Mortelmans et al, 2016 )]. The phenotypic effects of ERVs on the post-reproductive adult, however, remain unclear and are of growing interest (Li et al, 2015 ; Bowen et al, 2016 ; Sekar et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

To ERV Is Human: A Phenotype-Wide Scan Linking Polymorphic Human Endogenous Retrovirus-K Insertions to Complex Phenotypes

et al. 2018

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Approximately 8% of the human genome is comprised of endogenous retroviral insertions (ERVs) originating from historic retroviral integration into germ cells. The function of ERVs as regulators of gene expression is well established. Less well studied are insertional polymorphisms of ERVs and their contribution to the heritability of complex phenotypes. The most recent integration of ERV, HERV-K, is expressed in a range of complex human conditions from cancer to neurologic diseases. Using an in-house computational pipeline and whole-genome sequencing data from the diverse 1,000 Genomes Phase 3 population (n = 2,504), we identified 46 polymorphic HERV-K insertions that are tagged by adjacent single nucleotide polymorphisms (SNPs). To test the potential role of polymorphic HERV-K in the heritability of complex diseases, existing databases were queried for enrichment of established relationships between the HERV-K insertion-associated SNPs (hiSNPs), and tissue specific gene expression and disease phenotypes. Overall, hiSNPs for the 46 polymorphic HERV-K sites were statistically enriched (p < 1.0E−16) for eQTLs across 44 human tissues. Fifteen of the 46 HERV-K insertions had hiSNPs annotated in the EMBL-EBI GWAS Catalog and cumulatively associated with >100 phenotypes. Experimental factor ontology enrichment analysis suggests that polymorphic HERV-K specifically contribute to neurologic and immunologic disease phenotypes, including traits related to intra cranial volume (FDR 2.00E-09), Parkinson's disease (FDR 1.80E-09), and autoimmune diseases (FDR 1.80E-09). These results provide strong candidates for context-specific study of polymorphic HERV-K insertions in disease-related traits, serving as a roadmap for future studies of the heritability of complex disease.

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“…HERV-K was recently shown to be activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and the expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Excitingly, expression of HERV-K is regulated by TAR (trans-activation responsive) DNA binding protein 43, the main aggregating protein in sporadic ALS, which binds to the long terminal repeat region of the virus [50,56,57]. Thus, viral infections might represent environmental risk factors of and possible contributors to ALS pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Genome Wide Analysis Points towards Subtype-Specific Diseases in Different Genetic Forms of Amyotrophic Lateral Sclerosis

Dash

Naumann

Sterneckert

et al. 2020

IJMS

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Amyotropic lateral sclerosis (ALS) is a lethally progressive and irreversible neurodegenerative disease marked by apparent death of motor neurons present in the spinal cord, brain stem and motor cortex. While more and more gene mutants being established for genetic ALS, the vast majority suffer from sporadic ALS (>90%). It has been challenging, thus, to model sporadic ALS which is one reason why the underlying pathophysiology remains elusive and has stalled the development of therapeutic strategies of this progressive motor neuron disease. To further unravel these pathological signaling pathways, human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from FUS- and SOD1 ALS patients and healthy controls were systematically compared to independent published datasets. Here through this study we created a gene profile of ALS by analyzing the DEGs, the Kyoto encyclopedia of Genes and Genomes (KEGG) pathways, the interactome and the transcription factor profiles (TF) that would identify altered molecular/functional signatures and their interactions at both transcriptional (mRNAs) and translational levels (hub proteins and TFs). Our findings suggest that FUS and SOD1 may develop from dysregulation in several unique pathways and herpes simplex virus (HSV) infection was among the topmost predominant cellular pathways connected to FUS and not to SOD1. In contrast, SOD1 is mainly characterized by alterations in the metabolic pathways and alterations in the neuroactive-ligand–receptor interactions. This suggests that different genetic ALS forms are singular diseases rather than part of a common spectrum. This is important for patient stratification clearly pointing towards the need for individualized medicine approaches in ALS.

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HIV-associated motor neuron disease

Cited by 69 publications

References 30 publications

Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology

To ERV Is Human: A Phenotype-Wide Scan Linking Polymorphic Human Endogenous Retrovirus-K Insertions to Complex Phenotypes

Genome Wide Analysis Points towards Subtype-Specific Diseases in Different Genetic Forms of Amyotrophic Lateral Sclerosis

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