Endogenous Retroviruses and Cancer

Dudley, Jaquelin P.; Mertz, Jennifer A.; Bhadra, Sanchita; Palmarini, Massimo; Kozak, Christine A.

doi:10.1007/978-0-387-09581-3_5

Cited by 4 publications

(4 citation statements)

References 265 publications

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“…It is unclear whether ERV-DCs are harmful or beneficial to the host. However, previous studies have indicated that the presence of other ERVs in vertebrates is associated with protection against infection of related exogenous retroviruses as well as with the generation of pathogenic viruses or tumors (9,25,28). Our studies further indicate that ERV-DC10 was not able to produce infectious particles when it was present in some cell types, including feline PBMCs (ERV-DC10 ϩ/ϩ genotype) and the feline fibroblast cell line AH927 (ERV-DC10 ϩ/ϩ ), suggesting that the ERV-DC10 promoter can be modified in a tissue-specific manner, similar to the endogenous human ERV syncytin (23), as expression of retroviral genes can be controlled by transcriptional modification (43).…”

Section: Discussionmentioning

confidence: 99%

Infectious Endogenous Retroviruses in Cats and Emergence of Recombinant Viruses

Anai

Ochi

Watanabe

et al. 2012

J Virol

189

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bEndogenous retroviruses (ERVs) comprise a significant percentage of the mammalian genome, and it is poorly understood whether they will remain as inactive genomes or emerge as infectious retroviruses. Although several types of ERVs are present in domestic cats, infectious ERVs have not been demonstrated. Here, we report a previously uncharacterized class of endogenous gammaretroviruses, termed ERV-DCs, that is present and hereditary in the domestic cat genome. We have characterized a subset of ERV-DC proviral clones, which are numbered according to their genomic insertions. One of these, ERV-DC10, located in the q12-q21 region on chromosome C1, is an infectious gammaretrovirus capable of infecting a broad range of cells, including human. Our studies indicate that ERV-DC10 entered the genome of domestic cats in the recent past and appeared to translocate to or reintegrate at a distinct locus as infectious ERV-DC18. Insertional polymorphism analysis revealed that 92 of 244 domestic cats had ERV-DC10 on a homozygous or heterozygous locus. ERV-DC-like sequences were found in primate and rodent genomes, suggesting that these ERVs, and recombinant viruses such as RD-114 and BaEV, originated from an ancestor of ERV-DC. We also found that a novel recombinant virus, feline leukemia virus subgroup D (FeLV-D), was generated by ERV-DC env transduction into feline leukemia virus in domestic cats. Our results indicate that ERV-DCs behave as donors and/or acceptors in the generation of infectious, recombinant viruses. The presence of such infectious endogenous retroviruses, which could be harmful or beneficial to the host, may affect veterinary medicine and public health.

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Section: Discussionmentioning

confidence: 99%

Infectious Endogenous Retroviruses in Cats and Emergence of Recombinant Viruses

Anai

Ochi

Watanabe

et al. 2012

J Virol

189

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“…Naturally occurring infectious and endogenous MLVs of laboratory mice and wild mice are linked to a variety of neoplastic, immunological, and neurological diseases (64,68). In the XP-MLV family, recombinant P-MLVs derived from naturally occurring or laboratory MLV strains are pathogenic in mice (69), but there is limited work on the pathogenic potential of X-MLVs in mice because the belief that all mice are resistant to these viruses was only recently dispelled (70,71).…”

Section: Discussionmentioning

confidence: 99%

The Avian XPR1 Gammaretrovirus Receptor Is under Positive Selection and Is Disabled in Bird Species in Contact with Virus-Infected Wild Mice

Martin

Buckler-White

Wollenberg

et al. 2013

J Virol

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Xenotropic mouse leukemia viruses (X-MLVs) are broadly infectious for mammals except most of the classical strains of laboratory mice. These gammaretroviruses rely on the XPR1 receptor for entry, and the unique resistance of laboratory mice is due to two mutations in different putative XPR1 extracellular loops. Cells from avian species differ in susceptibility to X-MLVs, and 2 replacement mutations in the virus-resistant chicken XPR1 (K496Q and Q579E) distinguish it from the more permissive duck and quail receptors. These substitutions align with the two mutations that disable the laboratory mouse XPR1. Mutagenesis of the chicken and duck genes confirms that residues at both sites are critical for virus entry. Among 32 avian species, the 2 disabling XPR1 mutations are found together only in the chicken, an omnivorous, ground-dwelling fowl that was domesticated in India and/or Southeast Asia, which is also where X-MLV-infected house mice evolved. The receptor-disabling mutations are also present separately in 5 additional fowl and raptor species, all of which are native to areas of Asia populated by the virus-infected subspecies Mus musculus castaneus. Phylogenetic analysis showed that the avian XPR1 gene is under positive selection at sites implicated in receptor function, suggesting a defensive role for XPR1 in the avian lineage. Contact between bird species and virus-infected mice may thus have favored selection of mouse virus-resistant receptor orthologs in the birds, and our data suggest that similar receptor-disabling mutations were fixed in mammalian and avian species exposed to similar virus challenges.T he transmission of retroviruses to new hosts can result in the emergence of new infectious diseases and can alter the host genomic architecture and gene-regulatory networks, but the factors that determine whether a pathogen can successfully infect a novel host are poorly understood (1). The xenotropic mouse leukemia viruses (X-MLVs) are gammaretroviruses originally isolated from laboratory mice that are unable to infect the cells of these mice (2). These viruses rely on the XPR1 cell surface receptor for entry (3-5), and receptor orthologs from other mammals, like humans and cats, as well as the various species of wild mice, all permit X-MLV entry (6, 7). The resistance of laboratory mouse cells to infection is due to mutations that alter two XPR1 residues, K500E in the putative third extracellular loop (ECL3) and T582⌬ in the fourth loop (ECL4) (8).There is substantial sequence variation in the receptor-determining regions of the mammalian XPR1 orthologs, and some of these receptor variants show altered ability to mediate entry of one or more of the 6 known host range variants in the XP-MLV family of xenotropic/polytropic viruses (6, 9). In addition to X-MLV, this family includes viruses first described as broadly polytropic (PMLVs) because of their ability to infect mouse cells, as well as cells of other species (10, 11). Other variants, like xenotropic murine leukemia virus-related virus (XMRV) (12) an...

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“…Whilst most ERVs are defective and have degenerated over time, others have retained some or all of their open reading frames (ORFs) and can encode potentially pathogenic viral proteins [ 10 – 13 ]. These elements are normally suppressed in healthy tissues but expression has been reported in animal and human cancers [ 14 – 17 ]. The HERV-K (HML2) family (hereafter shortened to HERV-K) is remarkable in that it has recently amplified in humans and many of its ORFs are intact, making it the largest contributor of retroviral-derived proteins in the genome [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion

et al. 2017

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Endogenous retroviruses are cellular genes of retroviral origin captured by their host during the course of evolution and represent around 8% of the human genome. Although most are defective and transcriptionally silenced, some are still able to generate retroviral-like particles and proteins. Among these, the HERV-K(HML2) family is remarkable since its members have amplified relatively recently and many of them still have full length coding genes. Furthermore, they are induced in cancers, especially in melanoma, breast cancer and germ cell tumours, where viral particles, as well as the envelope protein (Env), can be detected. Here we show that HERV-K(HML2) Env per se has oncogenic properties. Its expression in a non-tumourigenic human breast epithelial cell line induces epithelial to mesenchymal transition (EMT), often associated with tumour aggressiveness and metastasis. In our model, this is typified by key modifications in a set of molecular markers, changes in cell morphology and enhanced cell motility. Remarkably, microarrays performed in 293T cells reveal that HERV-K(HML2) Env is a strong inducer of several transcription factors, namely ETV4, ETV5 and EGR1, which are downstream effectors of the MAPK ERK1/2 and are associated with cellular transformation. We demonstrate that HERV-K(HML2) Env effectively activates the ERK1/2 pathway in our experimental setting and that this activation depends on the Env cytoplasmic tail. In addition, this phenomenon is very specific, being absent with every other retroviral Env tested, except for Jaagsiekte Sheep Retrovirus (JSRV) Env, which is already known to have transforming properties in vivo. Though HERV-K Env is not directly transforming by itself, the newly discovered properties of this protein may contribute to oncogenesis.

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Endogenous Retroviruses and Cancer

Cited by 4 publications

References 265 publications

Infectious Endogenous Retroviruses in Cats and Emergence of Recombinant Viruses

Infectious Endogenous Retroviruses in Cats and Emergence of Recombinant Viruses

The Avian XPR1 Gammaretrovirus Receptor Is under Positive Selection and Is Disabled in Bird Species in Contact with Virus-Infected Wild Mice

A human endogenous retrovirus-derived gene that can contribute to oncogenesis by activating the ERK pathway and inducing migration and invasion

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