Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci

Nexø, Bjørn A.; Villesen, Palle; Nissen, Kari Konstantin; Lindegaard, Hanne; Rossing, Peter; Petersen, Thor; Tarnow, Lise; Hansen, Bettina; Lorenzen, Tove; Hørslev‐Petersen, Kim; Jensen, Sara B; Bahrami, Shervin; Lajer, Maria; Schmidt, Kathrine L.M.; Parving, Hans Henrik; Junker, Peter; Laska, Magdalena Janina

doi:10.1007/s12026-015-8671-z

Cited by 43 publications

(37 citation statements)

References 34 publications

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“…Our detailed investigation of LGL genomes from 11 leukemia patients (S1-S11) failed to detect a novel retrovirus integration site in circulating LGL that could elicit this antibody response, but we did identify several HERV-Ks that are polymorphic in humans and absent from the human reference genome. Endogenous retroviruses have been implicated in several cancers including leukemia [25, 26] and immune response to HERV proteins has been reported in both cancer and autoimmune diseases [27–29]. Of the reported polymorphic HERV-K, 16 are close to full length [17, 22].…”

Section: Resultsmentioning

confidence: 99%

Retrovirus insertion site analysis of LGL leukemia patient genomes

Yang

Harris

et al. 2019

Preprint

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23Background: Large granular lymphocyte (LGL) leukemia is an uncommon cancer characterized 24 by a sustained clonal proliferation of LGL cells. Antibodies reactive to retroviruses have been 25 documented in the serum of patients with LGL leukemia. Culture or molecular approaches have 26 to date not been successful in identifying a retrovirus. 27 Methods: Because a retrovirus must integrate into the genome of an infected cell, we focused 28 our efforts on detecting a novel retrovirus integration site in the clonally expanded LGL cells. 29We present a new computational tool that uses long-insert mate pair sequence data to search the 30 genome of LGL leukemia cells for retrovirus integration sites. We also utilize recently published 31 methods to interrogate the status of polymorphic human endogenous retrovirus type K (HERV-K) 32 provirus in patient genomes. 33Results: While our analysis did not reveal any new retrovirus insertions in LGL genomes from 34LGL leukemia patients, we did identify four HERV-K provirus integration sites that are 35 polymorphic in the human population and absent from the human reference genome, hg19. To 36 determine if the prevalence of these or other polymorphic proviral HERV-Ks differed between 37LGL leukemia patients and the general population, we applied a recently developed approach 38 that reports all sites in the human genome occupied by a proviral HERV-K. Using the 1000 39 genomes project (KGP) data as a reference database for HERV-K proviral prevalence at each 40 polymorphic site, we show that there are significant differences in the number of polymorphic 41 HERV-Ks in the genomes of LGL leukemia patients of European origin compared to individuals 42 with European ancestry in the KGP data. 43 Conclusions:Our study confirms that the integration of a new infectious or endogenous 44 retrovirus does not cause the clonal expansion of LGL cells in LGL leukemia, although we do 45 3 not rule out that these cells could be responding to retroviral antigens produced in other cell 46 types. However, it is of interest that the burden of polymorphic proviral HERV-K is elevated in 47LGL leukemia patient genomes. Our research emphasizes the merits of comprehensive genomic 48 assessment of HERV-K in cancer samples and suggests that further analyses to determine 49 contributions of HERV-K to LGL leukemia are warranted. 50 Keywords: Large granular lymphocyte leukemia, retrovirus, HERV-K, genomic insertion, 51 visualization tool 52 53 Background 54 Large granular lymphocyte (LGL) leukemia is a rare, chronic, proliferative disorder of cytotoxic 55 T cells (approximately 85% of cases) and NK cells [1]. Diagnosis of this leukemia is based on a 56 sustained elevation of a clonally expanded T or NK cell population. LGL leukemia is reported 57 most frequently in patients from North America and Europe and up to half of patients also have 58 an autoimmune disorder, most frequently rheumatoid arthritis [2]. A small subset of patients 59 show clonal proliferation of CD4+ cells, which has been associated with Cy...

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Section: Resultsmentioning

confidence: 99%

Retrovirus insertion site analysis of LGL leukemia patient genomes

Yang

Harris

et al. 2019

Preprint

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“…Telescope will have widespread utility in other settings. Studies on TE expression have become prominent in studies of embryonic stem cell development (Grow et al 2015)(Göke et al 2015), neural cell plasticity (Muotri et al 2010; Gage and Muotri 2012), oncogenesis (Wang-Johanning et al 2003; Rakoff-Nahoum et al 2006; Takahashi et al 2008; Tang et al 2017; Rodic et al 2015; Ardeljan et al 2017), psychiatric and neurological disorders(Perron et al 2012; Christensen 2016; Mortelmans et al 2016) and autoimmune diseases (Nexø et al 2015; Hanke et al 2016). As the breadth of knowledge on TEs expands, expression profiling of TEs using Telescope will allow scientists to discover unique and collective TE transcripts involved in the biology of complex systems.…”

Section: Discussionmentioning

confidence: 99%

Telescope: Characterization of the retrotranscriptome by accurate estimation of transposable element expression

Bendall

Mulder

Íñiguez

et al. 2018

Preprint

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1Characterization of Human Endogenous Retrovirus (HERV) expression within the 2 transcriptomic landscape using RNA-seq is complicated by uncertainty in fragment 3 assignment because of sequence similarity. We present Telescope, a computational 4 software tool that provides accurate estimation of transposable element expression 5 (retrotranscriptome) resolved to specific genomic locations. Telescope directly addresses 6 uncertainty in fragment assignment by reassigning ambiguously mapped fragments to the 7 most probable source transcript as determined within a Bayesian statistical model. We 8 demonstrate the utility of our approach through single locus analysis of HERV expression 9 in 13 ENCODE cell types. When examined at this resolution, we find that the magnitude 10

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“…Hypermethylation of a Cluster of KRAB-ZFP genes on Chromosome 19 in cancer (Lleras et al, 2011) reveals a role of endogenous retroviruses in cancer and aging because both have similar patterns of hypermethylation. For example, activation of HERV-K envelope protein is essential for tumorigenesis and metastasis of breast cancer cells (Zhou et al, 2016) due to stimulation of the innate immune system by endogenous viruses and therefore initiating the autoimmune response (Nexø et al, 2016). Transmembrane unit in the envelope of endogenous viruses also induces immunosuppression to evade the adaptive immune response promoting inability of adaptive immune system to suppress tumors (Morozov et al, 2013).…”

Section: Chronic Inflammation Interactions With Endogenous Retrovirusesmentioning

confidence: 99%

An analysis of the mechanism of aging: endogenous viral stimulus and the deleterious effect of chronic inflammation

Ochirov¹

2019

Preprint

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This article describes a putative mechanism of aging based on the interaction of endogenous viral particles with the receptors of the innate immune system leading to producing pro-inflammatory cytokines. The innate immune response induces a complex of signaling pathways leading to senescence or tumorigenesis. The fate of a cell is depended on the activity of the p53 tumor-suppressive signaling pathway. Chronic inflammation is characterized by upregulation of the NF-kB signaling. The NF-kB protein stimulates the expression of matrix metalloproteinases (MMPs) leading to remodeling of extracellular matrix. The extracellular matrix alterations induce the loss of stem cell environment and their depletion. The innate immune system also mediates the PI3K-Akt-mTOR signaling pathway that inhibits autophagy and transforms energy metabolism providing cell senescence, high level of blood glucose, high lipid synthesis and mitochondrial alterations. The STAT3-HIF1 signaling pathway suppresses oxidative phosphorylation increasing ROS production and promoting the MAPK pathway leading to excessive cell proliferation. The increased ROS production causes the global DNA and histone demethylation contributing to retrotransposon reactivation whose activity leads to genome instability. However, the activity of retrotransposons may be partly explained by their role in adaptation. Among retrotransposons, endogenous retroviruses may be considered as an intrinsic stimulus for the innate immune system and are also able to avoid the adaptive immune system. Therefore, I consider endogenous retroviruses as promising targets in anti-aging therapies

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Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci

Cited by 43 publications

References 34 publications

Retrovirus insertion site analysis of LGL leukemia patient genomes

Retrovirus insertion site analysis of LGL leukemia patient genomes

Telescope: Characterization of the retrotranscriptome by accurate estimation of transposable element expression

An analysis of the mechanism of aging: endogenous viral stimulus and the deleterious effect of chronic inflammation

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