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1.
Virol J ; 14(1): 9, 2017 01 14.
Article in English | MEDLINE | ID: mdl-28088235

ABSTRACT

Retroviruses are known to rely extensively on the expression of viral proteins from the sense proviral genomic strand. Yet, the production of regulatory retroviral proteins from antisense-encoded viral genes is gaining research attention, due to their clinical significance. This report will discuss what is known about antisense transcription in Retroviridae, and provide new information about antisense transcriptional regulation through a comparison of Human Immunodeficiency Virus (HIV), Human T-cell Lymphotrophic Virus (HTLV-1) and endogenous retrovirus-K (ERVK) long terminal repeats (LTRs). We will attempt to demonstrate that the potential for antisense transcription is more widespread within retroviruses than has been previously appreciated, with this feature being the rule, rather than the exception.


Subject(s)
Endogenous Retroviruses/genetics , Gene Expression Regulation, Viral , HIV/genetics , Human T-lymphotropic virus 1/genetics , Transcription, Genetic , Humans , Retroviridae
2.
J Virol ; 90(20): 9338-49, 2016 10 15.
Article in English | MEDLINE | ID: mdl-27512062

ABSTRACT

UNLABELLED: Thousands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription. Bioinformatic analysis suggests that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors. Here we show that one reason for ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon-stimulated response elements (ISREs) in the viral promoter. Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-κB isoforms. Tumor necrosis factor alpha (TNF-α) and LIGHT cytokine treatments of human astrocytes and neurons enhanced ERVK transcription and protein levels through IRF1 and NF-κB binding to the ISREs. We further show that in ALS brain tissue, neuronal ERVK reactivation is associated with the nuclear translocation of IRF1 and NF-κB isoforms p50 and p65. ERVK overexpression can cause motor neuron pathology in murine models. Our results implicate neuroinflammation as a key trigger of ERVK provirus reactivation in ALS. These molecular mechanisms may also extend to the pathobiology of other ERVK-associated inflammatory diseases, such as cancers, HIV infection, rheumatoid arthritis, and schizophrenia. IMPORTANCE: It has been well established that inflammatory signaling pathways in ALS converge at NF-κB to promote neuronal damage. Our findings suggest that inflammation-driven IRF1 and NF-κB activity promotes ERVK reactivation in neurons of the motor cortex in ALS. Thus, quenching ERVK activity through antiretroviral or immunomodulatory regimens may hinder virus-mediated neuropathology and improve the symptoms of ALS or other ERVK-associated diseases.


Subject(s)
Endogenous Retroviruses/genetics , Interferon Regulatory Factor-1/metabolism , Interferons/metabolism , NF-kappa B/metabolism , Response Elements/genetics , Terminal Repeat Sequences/genetics , Aged , Aged, 80 and over , Cells, Cultured , Endogenous Retroviruses/metabolism , Female , Gene Expression Regulation/genetics , HEK293 Cells , Humans , Inflammation/genetics , Inflammation/virology , Interferon-gamma/metabolism , Male , Middle Aged , Promoter Regions, Genetic/genetics , Signal Transduction/genetics , Transcription, Genetic/genetics , Transcriptional Activation/genetics , Tumor Necrosis Factor-alpha/metabolism
3.
Neurobiol Dis ; 94: 226-36, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27370226

ABSTRACT

The concomitant expression of neuronal TAR DNA binding protein 43 (TDP-43) and human endogenous retrovirus-K (ERVK) is a hallmark of ALS. Since the involvement of TDP-43 in retrovirus replication remains controversial, we sought to evaluate whether TDP-43 exerts an effect on ERVK expression. In this study, TDP-43 bound the ERVK promoter in the context of inflammation or proteasome inhibition, with no effect on ERVK transcription. However, over-expression of ALS-associated aggregating forms of TDP-43, but not wild-type TDP-43, significantly enhanced ERVK viral protein accumulation. Human astrocytes and neurons further demonstrated cell-type specific differences in their ability to express and clear ERVK proteins during inflammation and proteasome inhibition. Astrocytes, but not neurons, were able to clear excess ERVK proteins through stress granule formation and autophagy. In vitro findings were validated in autopsy motor cortex tissue from patients with ALS and neuro-normal controls. We further confirmed marked enhancement of ERVK in cortical neurons of patients with ALS. Despite evidence of enhanced stress granule and autophagic response in ALS cortical neurons, these cells failed to clear excess ERVK protein accumulation. This highlights how multiple cellular pathways, in conjunction with disease-associated mutations, can converge to modulate the expression and clearance of viral gene products from genomic elements such as ERVK. In ALS, ERVK protein aggregation is a novel aspect of TDP-43 misregulation contributing towards the pathology of this neurodegenerative disease.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , DNA-Binding Proteins/metabolism , Endogenous Retroviruses/metabolism , Motor Neurons/virology , Aged , Aged, 80 and over , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/virology , Astrocytes/metabolism , Astrocytes/virology , Autophagy/physiology , Female , Humans , Male , Middle Aged , Motor Neurons/pathology , Mutation/genetics , Viral Proteins/metabolism
4.
Front Microbiol ; 6: 1244, 2015.
Article in English | MEDLINE | ID: mdl-26617584

ABSTRACT

Due to multiple ancestral human retroviral germ cell infections, the modern human genome is strewn with relics of these infections, termed endogenous retroviruses (ERVs). ERV expression has been silenced due to negative selective pressures and genetic phenomena such as mutations and epigenetic silencing. Nonetheless, select ERVs have retained the capacity to be damaging to their host when reawakened. Much of the current research on the ERVK Env protein strongly suggests a causal or contributive role in the pathogenesis of various cancers, autoimmune and infectious diseases. Additionally, there is a small body of research suggesting that ERVK Env has been domesticated for use in placental development, akin to the ERVW syncytin. Though much is left to ascertain, the innate immune response to ERVK Env expression has been partially characterized and appears to be due to a region located in the transmembrane domain of the Env protein. In this review, we aim to highlight ERVK Env as a biomarker for inflammatory conditions and explore its use as a future therapeutic target for cancers, HIV infection and neurological disease.

5.
Viruses ; 7(1): 320-32, 2015 Jan 20.
Article in English | MEDLINE | ID: mdl-25609305

ABSTRACT

Enhanced expression of the reverse transcriptase (RT) protein encoded by human endogenous retrovirus-K (ERVK) is a promising biomarker for several inflammatory and neurological diseases. However, unlike RT enzymes encoded by exogenous retroviruses, little work has been done to identify ERVK RT isoforms, their expression patterns, and cellular localization. Using Western blot, we showcase the ERVK gag-pro-pol polyprotein processing leading to the production of several ERVK RT isoforms in human neuronal (ReNcell CX) and astrocytic (SVGA) models of neuroinflammatory disease. Since the pro-inflammatory cytokine IFNγ plays a key role in the pathology of several ERVK-associated neurological diseases, we sought to determine if IFNγ can drive ERVK RT expression. IFNγ signalling markedly enhanced ERVK polyprotein and RT expression in both human astrocytes and neurons. RT isoforms were expressed in a cell-type specific pattern and the RT-RNase H form was significantly increased with IFNγ treatment. Fluorescent imaging revealed distinct cytoplasmic, perinuclear and nuclear ERVK RT staining patterns upon IFNγ stimulation of astrocytes and neurons. These findings indicate that ERVK expression is inducible under inflammatory conditions such as IFNγ exposure-and thus, these newly established in vitro models may be useful in exploring ERVK biology in the context of neuroinflammatory disease.


Subject(s)
Endogenous Retroviruses/enzymology , Gene Expression Profiling , Gene Expression Regulation/drug effects , Polyproteins/analysis , RNA-Directed DNA Polymerase/analysis , Astrocytes/chemistry , Astrocytes/virology , Blotting, Western , Cell Line , Endogenous Retroviruses/genetics , Humans , Interferon-gamma/metabolism , Microscopy, Fluorescence , Neurons/chemistry , Neurons/virology , Polyproteins/genetics , Protein Isoforms/analysis , Protein Isoforms/genetics , RNA-Directed DNA Polymerase/genetics
6.
Curr Neurol Neurosci Rep ; 14(10): 488, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25138026

ABSTRACT

A new appreciation of the microbiome is changing the way we perceive human health and disease. The holobiontic nature of humans is even etched into our DNA in the form of viral symbionts. Empirical evidence for the presence of endogenous retroviruses (ERVs) in the human genome and their activity in homeostatic and pathologic states has accumulated; however, no causal relationship with human disease has been established to date. In this review, we will focus on the role of endogenous retrovirus-K in neurologic disease. Specifically, we will attempt to reconcile the pathologic contribution of ERVK in disparate neurologic diseases by providing evidence as to inter-individual differences in ERVK genotypes, addressing the molecular regulation of ERVK, and provide detailed examples of ERVK-mediated processes in nervous system diseases.


Subject(s)
Endogenous Retroviruses/genetics , Nervous System Diseases/virology , Endogenous Retroviruses/physiology , Humans , Nervous System Diseases/genetics , Phenotype , Transcription Factors/metabolism , Transcription, Genetic
7.
Retrovirology ; 10: 16, 2013 Feb 09.
Article in English | MEDLINE | ID: mdl-23394165

ABSTRACT

Humans are symbiotic organisms; our genome is populated with a substantial number of endogenous retroviruses (ERVs), some remarkably intact, while others are remnants of their former selves. Current research indicates that not all ERVs remain silent passengers within our genomes; re-activation of ERVs is often associated with inflammatory diseases. ERVK is the most recently endogenized and transcriptionally active ERV in humans, and as such may potentially contribute to the pathology of inflammatory disease. Here, we showcase the transcriptional regulation of ERVK. Expression of ERVs is regulated in part by epigenetic mechanisms, but also depends on transcriptional regulatory elements present within retroviral long terminal repeats (LTRs). These LTRs are responsive to both viral and cellular transcription factors; and we are just beginning to appreciate the full complexity of transcription factor interaction with the viral promoter. In this review, an exploration into the inflammatory transcription factor sites within the ERVK LTR will highlight the possible mechanisms by which ERVK is induced in inflammatory diseases.


Subject(s)
Endogenous Retroviruses/genetics , Inflammation/virology , Promoter Regions, Genetic , Transcription Factors/metabolism , Humans , Inflammation/pathology , Protein Binding , Transcription, Genetic
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