Human endogenous retrovirus-K (HML-2): a comprehensive review

García-Montojo, Marta; Doucet-O’Hare, Tara T.; Henderson, Lee A.; Nath, Avindra

doi:10.1080/1040841x.2018.1501345

Cited by 161 publications

(189 citation statements)

References 204 publications

(278 reference statements)

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“…4E). We also observed an upregulation of the np9 and rec alternative transcripts, which encode for proteins with oncogenic potential and promoting expression of the IFITM1 antiviral factor (21)(22)(23)(24)(25). As well, KZFP-depleted iN were characterized by the upregulation of IFNγ and ISGs such as TNF, IFITMs, APOBEC3B, IRF1, IFIH1 (a.k.a.…”

mentioning

confidence: 76%

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

Trono

Turelli

Playfoot

et al. 2019

Preprint

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In the first days of embryogenesis, transposable element-embedded regulatory sequences (TEeRS) are silenced by Kruppel-associated box (KRAB)-zinc finger proteins (KZFPs).Many TEeRS are subsequently coopted in transcription networks, but how KZFPs influence this process is largely unknown. We identify ZNF417 and ZNF587 as primate-specific KZFPs repressing HERVK (human endogenous retrovirus K) and SVA (SINE-VNTR-Alu) integrants in human embryonic stem cells (ESC). Expressed in specific regions of the human developing and adult brain, ZNF417/587 keep controlling TEeRS in ESC-derived neurons and brain organoids, secondarily influencing the differentiation and neurotransmission profile of neurons and preventing the induction of neurotoxic retroviral proteins and an interferonlike response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology.One Sentence Summary: Young transposable elements and their protein controllers team up to regulate the differentiation and function of human neurons. Main Text:Some 4.5 million transposable element (TE)-derived sequences are disseminated across the human genome, many of which integrated within the last few tens of million years (1). TEs are typically enriched in transcription factor (TF) binding sites, and correspondingly influence gene expression in a broad range of biological events (2-5). However, TEeRS are silenced during the earliest phase of embryogenesis by KZFPs, which dock KAP1 (KRAB-associated protein 1, a.k.a. TRIM28) and associated heterochromatin inducers to TE loci (6-8). The rapid evolutionary selection of KZFP genes was initially interpreted as solely reflecting the host component of an arms race, but recent data suggest that KZFPs team up with TEs to build species-restricted layers of epigenetic regulation (8,9). The present work provides direct support for this model.We previously determined that a 35bp-long TE sequence encompassing the HERVK14C primer binding site (PBS)-encoding region (coined HERVK-R) confers KAP1-induced repression to a nearby PGK promoter in hESC (10). As part of a large-scale screen, we identified ZNF417 and ZNF587 as selectively enriched at loci containing this HERVK sequence (9). Depleting these two KZFPs from hESC restored expression of an HERVK-Rcontaining PGK-GFP lentivector (LV) (Fig. 1A), while producing them in murine ESCs silenced this vector, demonstrating the sequence-specific repressor potential of ZNF417 and ZNF587 and the likely absence of mouse orthologue ( fig. S1A). Phylogenetic analyses confirmed that ZNF417 emerged in the human ancestral genome ahead of the New World Monkey split 43 million years ago and that ZNF587 arose by duplication some 24 million years later ( fig. S1, B and C). ZNF417 and ZNF587 display 98% amino acid homology with some

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mentioning

confidence: 76%

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

Trono

Turelli

Playfoot

et al. 2019

Preprint

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“…Recently, HERV‐K has been suspected to contribute to various human diseases, such as cancer and amyotrophic lateral sclerosis, and reverse transcriptase activity, likely of retroelement origin, to Alzheimer's disease (AD) (see below).…”

Section: Endogenous Virusesmentioning

confidence: 99%

“…13 In addition, endogenous retroviruses have been shown to provide regulatory elements including transcription factor binding sites to mammalian genes, which, for example, have been shown to modulate innate immunity pathways. 12 Recently, HERV-K has been suspected to contribute to various human diseases, such as cancer and amyotrophic lateral sclerosis, 86 and reverse transcriptase activity, likely of retroelement origin, to Alzheimer's disease (AD) 87…”

Section: Endogenous Virusesmentioning

confidence: 99%

What viruses tell us about evolution and immunity: beyond Darwin?

Broecker

Moelling

2019

Annals of the New York Academy of Sciences

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We describe mechanisms of genetic innovation mediated by viruses and related elements that, during evolution, caused major genetic changes beyond what was anticipated by Charles Darwin. Viruses and related elements introduced genetic information and have shaped the genomes and immune systems of all cellular life forms. None of these mechanisms contradict Darwin's theory of evolution but extend it by means of sequence information that has recently become available. Not only do small increments of genetic information contribute to evolution, but also do major events such as infection by viruses or bacteria, which can supply new genetic information to a host by horizontal gene transfer. Thereby, viruses and virus‐like elements act as major drivers of evolution.

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“…This retrovirus group integrated into the human genome in the last 5 million years (9,10). Even though all HERV-K proviruses are defective in at least one gene, many of them have complete open reading frames, and all HERV-K viral proteins can be expressed from different loci in the human genome (11). Moreover, HERV-K can also form virus-like particles, particularly in cancer cells (12).…”

Section: Introductionmentioning

confidence: 99%

Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial

Gold

Rowe

Kiernan

et al. 2019

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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Background: Neuroinflammation and human endogenous retroviruses (HERV) are thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Therapy directed against endogenous retroviruses has demonstrated positive effects during in vitro and biomarker studies. Consequently, the present study was undertaken to assess the safety and tolerability of long-term antiretroviral therapy (ART), Triumeq (abacavir, lamivudine, and dolutegravir) exposure in patients with ALS, and efficacy against biomarkers of disease progression. Methods: Patients were observed during a 10week lead-in period before receiving Triumeq treatment for 24 weeks at four specialist ALS centers. The primary outcomes were safety and tolerability. Secondary outcomes included HERV-K expression levels, urinary p75 ECD levels, neurophysiological parameters, and clinical indicators. The ENCALS prediction model was applied to provide an estimate of the cohort survival. The trial was registered (NCT02868580). Findings: 40 patients with ALS received Triumeq and 35 (88%) completed treatment. There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes. A favorable response on HERV-K expression levels was observed, accompanied by a decline in ALSFRS-R progression rate of 21.8% (95% CI À4.8%-48.6%) and the amount of urinary p75 ECD measured. One patient died five months after stopping treatment, while five were expected to have died during the treatment period (interquartile range 2-8). Interpretation: Long-term Triumeq exposure was safe and well tolerated in this cohort. There was suggestive indication for a possible biological response in some pharmacodynamic and clinical biomarkers. A larger international phase 3 trial will be deployed to assess the effect of Triumeq on overall survival and disease progression.

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Human endogenous retrovirus-K (HML-2): a comprehensive review

Cited by 161 publications

References 204 publications

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

What viruses tell us about evolution and immunity: beyond Darwin?

Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial

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