Endogenous Retroviruses as Targets for Antitumor Immunity in Renal Cell Cancer and Other Tumors

Cherkasova, Elena; Weisman, Quinn; Childs, Richard W.

doi:10.3389/fonc.2013.00243

Cited by 32 publications

(22 citation statements)

References 41 publications

(38 reference statements)

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“…As human ERVs are much older than MLV sequences in mice, it might be assumed that the host immune system would have evolved in concert and be unable to recognize human ERV nucleic acids or proteins as foreign. Nonetheless, some human ERV-encoded proteins have been shown to be immunogenic, with antibodies and cytotoxic T cells against ERV proteins being detected in some cancers (139). Although a true causative role for ERVs in autoimmune diseases is difficult to demonstrate, there is suggestive evidence (140,141,142).…”

Section: Auto-immune Disordersmentioning

confidence: 99%

Mammalian Endogenous Retroviruses

Mager

Stoye²

2015

Microbiol Spectr

171

103

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Over 40% of mammalian genomes comprise the products of reverse transcription. Among such retrotransposed sequences are those characterized by the presence of long terminal repeats (LTRs), including the endogenous retroviruses (ERVs), which are inherited genetic elements closely resembling the proviruses formed following exogenous retrovirus infection. Sequences derived from ERVs make up at least 8 to 10% of the human and mouse genomes and range from ancient sequences that predate mammalian divergence to elements that are currently still active. In this chapter we describe the discovery, classification and origins of ERVs in mammals and consider cellular mechanisms that have evolved to control their expression. We also discuss the negative effects of ERVs as agents of genetic disease and cancer and review examples of ERV protein domestication to serve host functions, as in placental development. Finally, we address growing evidence that the gene regulatory potential of ERV LTRs has been exploited multiple times during evolution to regulate genes and gene networks. Thus, although recently endogenized retroviral elements are often pathogenic, those that survive the forces of negative selection become neutral components of the host genome or can be harnessed to serve beneficial roles.

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Section: Auto-immune Disordersmentioning

confidence: 99%

Mammalian Endogenous Retroviruses

Mager

Stoye²

2015

Microbiol Spectr

171

103

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“…The family is important because expression of HK2 proteins is upregulated in a range of diseases, although it is not known whether it is involved in their causality or is a result of their pathophysiology [ 15 - 17 ]. This upregulation also raises the possibility of HK2 loci serving as immunotherapy targets in cancer and HIV therapy [ 18 - 20 ].…”

Section: Introductionmentioning

confidence: 99%

The decline of human endogenous retroviruses: extinction and survival

2015

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BackgroundEndogenous Retroviruses (ERVs) are retroviruses that over the course of evolution have integrated into germline cells and eventually become part of the host genome. They proliferate within the germline of their host, making up ~5% of the human and mouse genome sequences. Several lines of evidence have suggested a decline in the rate of ERV integration into the human genome in recent evolutionary history but this has not been investigated quantitatively or possible causes explored.ResultsBy dating the integration of ERV loci in 40 mammal species, we show that the human genome and that of other hominoids (great apes and gibbons) have experienced an approximately four-fold decline in the ERV integration rate over the last 10 million years. A major cause is the recent extinction of one very large ERV lineage (HERV-H), which is responsible for most of the integrations over the last 30 million years. The decline however affects most other ERV lineages. Only about 10% of the decline might be attributed to an accompanying increase in body mass (a trait we have shown recently to be negatively correlated with ERV integration rate). Humans are unusual compared to related species – Old World monkeys, great apes and gibbons – in (a) having not acquired any new ERV lineages during the last 30 million years and (b) the possession of an old ERV lineage that has continued to replicate up until at least the last few hundred thousand years – the potentially medically significant HERVK(HML2).ConclusionsThe human genome shares with the genome of other great apes and gibbons a recent decline in ERV integration that is not typical of other primates and mammals. The human genome differs from that of related species both in maintaining up until at least recently a replicating old ERV lineage and in not having acquired any new lineages. We speculate that the decline in ERV integration in the human genome has been exacerbated by a relatively low burden of horizontally-transmitted retroviruses and subsequent reduced risk of endogenization.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0136-x) contains supplementary material, which is available to authorized users.

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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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Endogenous Retroviruses as Targets for Antitumor Immunity in Renal Cell Cancer and Other Tumors

Cited by 32 publications

References 41 publications

Mammalian Endogenous Retroviruses

Mammalian Endogenous Retroviruses

The decline of human endogenous retroviruses: extinction and survival

Retrovirus insertion site analysis of LGL leukemia patient genomes

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