A computational framework to assess genome-wide distribution of polymorphic human endogenous retrovirus-K In human populations

Li, Weiling; Malhotra, Raunaq; Yang, Lei; Acharya, Raj; Poss, Mary

doi:10.1371/journal.pcbi.1006564

Cited by 29 publications

(40 citation statements)

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“…Endogenous retroviruses have been implicated in several cancers including leukemia [27–32] and immune response to HERV proteins has been reported in both cancer and autoimmune diseases [29, 30, 33, 34]. Of the reported polymorphic HERV-K, 16 are close to full length [18, 23]. However, the genomic profile of polymorphic HERV-K proviruses in cancer patients compared to the population at large is at present unknown.…”

Section: Resultsmentioning

confidence: 99%

“…However, the genomic profile of polymorphic HERV-K proviruses in cancer patients compared to the population at large is at present unknown. We thus investigated the distribution of polymorphic HERV-K in LGL leukemia patients and normal populations represented in the KGP data [18, 35].…”

Section: Resultsmentioning

confidence: 99%

“…Our detection method to identify retroviral insertions used in this paper depended on long insert mate pair sequencing, which is not typically available for the large genomic databases needed to determine the prevalence of polymorphic HERV-K in global populations. We recently reported on a method that utilizes unique k-mers present in each published HERV-K provirus to estimate the proviral prevalence of polymorphic HERV-K proviruses in any individual from paired-end sequence data [18]. The output of the pipeline is the ratio ( n/T ) of k-mers from a query set ( n ) to the total number of unique k-mers ( T ) for each HERV-K proviral insertion.…”

Section: Resultsmentioning

confidence: 99%

“…Endogenous retrovirus hits that had host flanking regions were confirmed to be from the candidate insertion site by mapping to the reference genome. A second method independent of the insertion call pipeline was used to confirm detected polymorphic HERV-K insertions (Additional file 1: Supplementary Methods and [18]). The code for the insertion call pipeline and simulation can be found at https://github.com/rsharris/suffynx

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Section: Methodsmentioning

confidence: 99%

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Retrovirus insertion site analysis of LGL leukemia patient genomes

Yang

Harris

et al. 2019

BMC Med Genomics

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Background Large granular lymphocyte (LGL) leukemia is an uncommon cancer characterized by sustained clonal proliferation of LGL cells. Antibodies reactive to retroviruses have been documented in the serum of patients with LGL leukemia. Culture or molecular approaches have to date not been successful in identifying a retrovirus. Methods Because a retrovirus must integrate into the genome of an infected cell, we focused our efforts on detecting a novel retrovirus integration site in the clonally expanded LGL cells. We present a new computational tool that uses long-insert mate pair sequence data to search the genome of LGL leukemia cells for retrovirus integration sites. We also utilize recently published methods to interrogate the status of polymorphic human endogenous retrovirus type K (HERV-K) provirus in patient genomes. Results Our data show that there are no new retrovirus insertions in LGL genomes of LGL leukemia patients. However, our insertion call tool did detect four HERV-K provirus integration sites that are polymorphic in the human population but absent from the human reference genome, hg19. To determine if the prevalence of these or other polymorphic proviral HERV-Ks differed between LGL leukemia patients and the general population, we used a recently developed tool that reports sites in the human genome occupied by a known proviral HERV-K. We report that there are significant differences in the number of polymorphic HERV-Ks in the genomes of LGL leukemia patients of European origin compared to individuals with European ancestry in the 1000 genomes (KGP) data. Conclusions Our study confirms that the clonal expansion of LGL cells in LGL leukemia is not driven by the integration of a new infectious or endogenous retrovirus, although we do not rule out that these cells are responding to retroviral antigens produced in other cell types. However, our computational analyses revealed that the genomes of LGL leukemia patients carry a higher burden of polymorphic HERV-K proviruses compare to individuals from KGP of European ancestry. Our research emphasizes the merits of comprehensive genomic assessment of HERV-K in cancer samples and suggests that further analyses to determine contributions of HERV-K to LGL leukemia are warranted. Electronic supplementary material The online version of this article (10.1186/s12920-019-0549-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Fig.…”

Section: Methodsmentioning

confidence: 99%

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Retrovirus insertion site analysis of LGL leukemia patient genomes

Yang

Harris

et al. 2019

BMC Med Genomics

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“…Proviral ERVs have gained growing interest due to their association with diseases such as cancer and neurodegenerative diseases, with particular emphasis on the ERV-K family of ERVs, also known as HML-2 (Schmitt et al, 2013b;Subramanian et al, 2011;Marta et al, 2019). ERV-Ks are the only ERVs that are human-specific with intact open reading frames that remain unfixed in the human population (Jha et al, 2011;Wildschutte et al, 2016;Li et al, 2019). In addition, ERV-Ks are the only ERV family that has been reported to generate viral-like proteins in teratocarcinoma cell line and human blastocysts (Löwer et al, 1993;Bhardwaj et al, 2015;Grow et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Antibody against envelope protein from human endogenous retrovirus activates neutrophils in systemic lupus erythematosus

Tokuyama

Gunn

Venkataraman

et al. 2019

Preprint

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eTOC summaryUsing ERVmap, the authors determined that the expression of ERV-K102 locus was elevated in SLE patient blood and correlated with the interferon signature. The envelope protein encoded by this locus activates human neutrophils through immune complex formation with SLE IgG. AbstractNeutrophil activation and the formation of neutrophil extracellular trap (NET) are hallmarks of innate immune activation in systemic lupus erythematosus (SLE) and contribute to the systemic interferon signature. Here we report that the expression of an endogenous retrovirus (ERV) locus ERV-K102, encoding an envelope protein, was significantly elevated in SLE patient blood and was correlated with higher interferon status. Induction of ERV-K102 expression most strongly correlated with reduced transcript levels of epigenetic silencing factors. SLE IgG promoted phagocytosis of ERV-K102 envelope protein by neutrophils through immune complex formation. ERV immune complex phagocytosis resulted in subsequent NET formation consisting of DNA, neutrophil elastase, and citrullinated histone H3. Finally, analysis of anti-ERV-K102 IgG in SLE patients showed that IgG2 likely mediates this effect. Together, we identified an immunostimulatory ERV-K envelope protein elevated in SLE that may be a target of SLE IgG and able to promote neutrophil activation. * * GST-Kenv

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Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis

Pandya

Pasternack

et al. 2022

Neurotherapeutics

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The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical transmissions of retroviral elements were key to the development of an ALS-like syndrome leading to the postulate that endogenous retroviruses (ERVs) contribute significantly to the pathogenicity of this disease. Subsequent studies identified retroviral reverse transcriptase activity in brains of individuals with ALS from Guam. However, except for a single study from the former Soviet Union, ALS could not be transmitted to rhesus macaques. The discovery of an ALS-like syndrome in human immunodeficiency virus (HIV) and human T cell leukemia virus infected individuals led to renewed interest in the field and reverse transcriptase activity was found in the blood and cerebrospinal fluid of individuals with sporadic ALS. However, exogenous retroviruses could not be found in individuals with ALS which further reinforced the possibility of involvement of a human ERV (HERV). The first demonstration of the involvement of a HERV was the discovery of the activation of human endogenous retrovirus-K subtype HML-2 in the brains of individuals with ALS. The envelope protein of HML-2 is neurotoxic and transgenic animals expressing the envelope protein develop an ALS-like syndrome. Activation of HML-2 occurs in the context of generalized transposable element activation and is not specific for ALS. Individuals with HIV-associated ALS show a remarkable response to antiretroviral therapy; however, antiretroviral trials in ALS down-regulate HML-2 without ameliorating the disease. This highlights the need for specific drugs to be developed against HML-2 as a novel therapeutic target for ALS. Other approaches might include antisense oligonucleotides, shRNA targeted against the envelope gene or antibodies that can target the extracellular envelope protein. Future clinical trials in ALS should consider combination therapies to control these ERVs.

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A computational framework to assess genome-wide distribution of polymorphic human endogenous retrovirus-K In human populations

Cited by 29 publications

References 59 publications

Retrovirus insertion site analysis of LGL leukemia patient genomes

Retrovirus insertion site analysis of LGL leukemia patient genomes

Antibody against envelope protein from human endogenous retrovirus activates neutrophils in systemic lupus erythematosus

Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis

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