Search Results (27)

The Genus Alpharetrovirus contains viruses pathogenic mainly for chickens, forming the Avian Sarcoma and Leukosis Virus group (ASLV). Cells of most Galliform species, besides chickens, contain genetic elements (endogenous retroviruses, ERVs) that could recombine with other alpharetroviruses or express proteins, complementing defective ASLV, which may successfully replicate and cause disease. However, they are quite unknown, and only ALV-F, from ring-necked pheasants, has been partially published. Upon scrutiny of 53 genomes of different avian species, we found Alpharetrovirus-like sequences only in 12 different Galliformes, including six full-length (7.4–7.6 Kbp) and 27 partial sequences. Phylogenetic studies of the regions studied (LTR, gag, pol, and env) consistently resulted in five almost identical clades containing the same ERVs: Clade I (presently known ASLVs); Clade II (Callipepla spp. ERVs); Clade IIIa (Phasianus colchicus ERVs); Clade IIIb (Alectoris spp. ERVs); and Clade IV (Centrocercus spp. ERVs). The low pol identity scores suggested that each of these Clades may be considered a different species. ORF analysis revealed that putatively encoded proteins would be very similar in length and domains to those of other alpharetroviruses and thus potentially functional. This will undoubtedly contribute to better understanding the biology of defective viruses, especially in wild Galliformes, their evolution, and the danger they may represent for other wild species and the poultry industry. Full article

Endogenous retroviruses (ERVs) account for 8% of our genome, and, although they are usually silent in healthy tissues, they become reactivated and expressed in pathological conditions such as cancer. Several studies support a functional role of ERVs in tumour development and progression, specifically through their envelope (Env) protein, which contains a region described as an immunosuppressive domain (ISD). We have previously shown that targeting of the murine ERV (MelARV) Env using virus-like vaccine (VLV) technology, consisting of an adenoviral vector encoding virus-like particles (VLPs), induces protection against small tumours in mice. Here, we investigate the potency and efficacy of a novel MelARV VLV with a mutated ISD (ISDmut) that can modify the properties of the adenoviral vaccine-encoded Env protein. We show that the modification of the vaccine’s ISD significantly enhanced T-cell immunogenicity in both prime and prime-boost vaccination regimens. The modified VLV in combination with an α-PD1 checkpoint inhibitor (CPI) exhibited excellent curative efficacy against large established colorectal CT26 tumours in mice. Furthermore, only ISDmut-vaccinated mice that survived CT26 challenge were additionally protected against rechallenge with a triple-negative breast cancer cell line (4T1), showing that our modified VLV provides cross-protection against different tumour types expressing ERV-derived antigens. We envision that translating these findings and technology into human ERVs (HERVs) could provide new treatment opportunities for cancer patients with unmet medical needs. Full article

Alveolar macrophages (AMs) form the first defense line against various respiratory pathogens, and their immune response has a profound impact on the outcome of respiratory infection. Enhancer of zeste homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attention for its immune regulation function, yet its exact function in AMs remains largely obscure. Using porcine 3D4/21 AM cells as a model, we characterized the transcriptomic and epigenomic alterations after the inhibition of EZH2. We found that the inhibition of EZH2 causes transcriptional activation of numerous immune genes and inhibits the subsequent infection by influenza A virus. Interestingly, specific families of transposable elements, particularly endogenous retrovirus elements (ERVs) and LINEs which belong to retrotransposons, also become derepressed. While some of the derepressed ERV families are pig-specific, a few ancestral families are known to be under EZH2-mediated repression in humans. Given that derepression of ERVs can promote innate immune activation through “viral mimicry”, we speculate that ERVs may also contribute to the coinciding immune activation in AMs after the inhibition of EZH2. Overall, this study improves the understanding of the EZH2-related immune regulation in AMs and provides novel insights into the epigenetic regulation of retrotransposons in pigs. Full article

The immune pathogenesis of multiple sclerosis (MS) is thought to be triggered by environmental factors in individuals with an unfavorable genetic predisposition. Epstein–Barr virus (EBV) infection is a major risk factor for subsequent development of MS. Human endogenous retroviruses (HERVs) can be activated by EBV, and might be a missing link between an initial EBV infection and the later onset of MS. In this study, we investigated differential gene expression patterns in EBV-immortalized lymphoblastoid B cell lines (LCL) from MS-affected individuals (MSLCL) and controls by using RNAseq and qRT-PCR. RNAseq data from LCL mapped to the human genome and a virtual virus metagenome were used to identify possible biomarkers for MS or disease-relevant risk factors, e.g., the relapse rate. We observed that lytic EBNA-1 transcripts seemed to be negatively correlated with age leading to an increased expression in LCL from younger PBMC donors. Further, HERV-K (HML-2) GAG was increased upon EBV-triggered immortalization. Besides the well-known transactivation of HERV-K18, our results suggest that another six HERV loci are up-regulated upon stimulation with EBV. We identified differentially expressed genes in MSLCL, e.g., several HERV-K loci, ERVMER61-1 and ERV3-1, as well as genes associated with relapses. In summary, EBV induces genes and HERV in LCL that might be suitable as biomarkers for MS or the relapse risk. Full article

Endogenous retroviruses (ERVs) are the remnants of ancient infections of host germline cells, thus representing key tools to study host and viral evolution. Homologous ERV sequences often map at the same genomic locus of different species, indicating that retroviral integration occurred in the genomes of the common ancestors of those species. The genome of domestic sheep (Ovis aries) harbors at least twenty-seven copies of ERVs related to the exogenous and pathogenic Jaagsiekte sheep retrovirus (JSRVs), thus referred to as enJSRVs. Some of these loci are unequally distributed between breeds and individuals of the host species due to polymorphic insertions, thereby representing invaluable tools to trace the evolutionary dynamics of virus populations within their hosts. In this study, we extend the cytogenetic physical maps of sheep and river buffalo by performing fluorescent in situ hybridization (FISH) mapping of twenty-three genetically characterized enJSRVs. Additionally, we report the first comparative FISH mapping of enJSRVs in domestic sheep (2n = 54) and river buffalo (Bubalus bubalis, 2n = 50). Finally, we demonstrate that enJSRV loci are conserved in the homologous chromosomes and chromosome bands of both species. Altogether, our results support the hypothesis that enJSRVs were present in the genomes of both species before they differentiated within the Bovidae family. Full article

A voluntary biosurveillance program was established in 2008 in order to determine the shedding frequency and prevalence factors for common respiratory pathogens associated with acute onset of fever and/or respiratory signs in equids from the USA. Over a period of 13 years, a total of 10,296 equids were enrolled in the program and nasal secretions were analyzed for the qPCR detection of equine influenza virus (EIV), equine herpesvirus-1 (EHV-1), EHV-4, equine rhinitis A and B virus (ERVs), and Streptococcus equi subspecies equi (S. equi). Single infections with respiratory pathogens were detected in 21.1% of the submissions with EIV (6.8%) and EHV-4 (6.6%) as the two most prevalent viruses, followed by S. equi (4.7%), ERVs (2.3%), and EHV-1 (0.7%). Multiple pathogens were detected in 274 horses (2.7%) and no respiratory pathogens in 7836 horses (76.2%). Specific prevalence factors were determined for each of the six respiratory pathogen groups; most differences were associated with age, breed, and use of the horses, while the clinical signs were fairly consistent between viral and bacterial respiratory infections. Monitoring the frequency of detection of common respiratory pathogens is important in order to gain a better understanding of their epidemiology and to implement management practices aimed at controlling disease spread. Full article

The classical laboratory mouse strains are genetic mosaics of three Mus musculus subspecies that occupy distinct regions of Eurasia. These strains and subspecies carry infectious and endogenous mouse leukemia viruses (MLVs) that can be pathogenic and mutagenic. MLVs evolved in concert with restrictive host factors with some under positive selection, including the XPR1 receptor for xenotropic/polytropic MLVs (X/P-MLVs) and the post-entry restriction factor Fv1. Since positive selection marks host-pathogen genetic conflicts, we examined MLVs for counter-adaptations at sites that interact with XPR1, Fv1, and the CAT1 receptor for ecotropic MLVs (E-MLVs). Results describe different co-adaptive evolutionary paths within the ranges occupied by these virus-infected subspecies. The interface of CAT1, and the otherwise variable E-MLV envelopes, is highly conserved; antiviral protection is afforded by the Fv4 restriction factor. XPR1 and X/P-MLVs variants show coordinate geographic distributions, with receptor critical sites in envelope, under positive selection but with little variation in envelope and XPR1 in mice carrying P-ERVs. The major Fv1 target in the viral capsid is under positive selection, and the distribution of Fv1 alleles is subspecies-correlated. These data document adaptive, spatial and temporal, co-evolutionary trajectories at the critical interfaces of MLVs and the host factors that restrict their replication. Full article

Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in demyelinating and neurodegenerative processes. Transposable elements (TEs) are DNA sequences that can move from one genomic location to another. TEs have been linked to several diseases affecting the central nervous system (CNS), including multiple sclerosis (MS), a demyelinating disease of unknown etiology influenced by genetic and environmental factors. Exogenous viral transactivators may activate certain retrotransposons or class I TEs. In this context, several herpesviruses have been linked to MS, and one of them, HSV-1, might act as a risk factor by mediating processes such as molecular mimicry, remyelination, and activity of endogenous retroviruses (ERVs). Several herpesviruses have been involved in the regulation of human ERVs (HERVs), and HSV-1 in particular can modulate HERVs in cells involved in MS pathogenesis. This review exposes current knowledge about the relationship between HSV-1 and human ERVs, focusing on their contribution as a risk factor for MS. Full article

Studies of viruses that coevolved with lemurs provide an opportunity to understand the basal traits of primate viruses and provide an evolutionary context for host-virus interactions. Germline integration of endogenous retroviruses (ERVs) are fossil evidence of past infections. Hence, characterization of novel ERVs provides insight into the ancient precursors of extant viruses and the evolutionary history of their hosts. Here, we report the discovery of a novel endogenous retrovirus present in the genome of a lemur, Coquerel’s sifaka (Propithecus coquereli). Using next-generation sequencing, we identified and characterized the complete genome sequence of a retrovirus, named prosimian retrovirus 1 (PSRV1). Phylogenetic analyses indicate that PSRV1 is a gamma-type betaretrovirus basal to the other primate betaretroviruses and most closely related to simian retroviruses. Molecular clock analysis of PSRV1 long terminal repeat (LTR) sequences estimated the time of endogenization within 4.56 MYA (±2.4 MYA), placing it after the divergence of Propithecus species. These results indicate that PSRV1 is an important milestone of lemur evolution during the radiation of the Propithecus genus. These findings may have implications for both human and animal health in that the acquisition of a gamma-type env gene within an endogenized betaretrovirus could facilitate a cross-species jump between vertebrate class hosts. Full article

Old World monkeys (OWM), simians inhabiting Africa and Asia, are currently affected by at least four infectious retroviruses, namely, simian foamy virus (SFV), simian immunodeficiency virus (SIV), simian T-lymphotropic virus (STLV), and simian type D retrovirus (SRV). OWM also show chromosomal evidence of having been infected in the past with four more retroviral species, baboon endogenous virus (BaEV), Papio cynocephalus endogenous virus (PcEV), simian endogenous retrovirus (SERV), and Rhesus endogenous retrovirus-K (RhERV-K/SERV-K1). For some of the viruses, transmission to other primates still occurs, resulting, for instance, in the HIV pandemic. Retroviruses are intimately connected with their host as they are normally spread by close contact. In this review, an attempt to reconstruct the distribution and history of OWM retroviruses will be made. A literature overview of the species infected by any of the eight retroviruses as well as an age estimation of the pathogens will be given. In addition, primate genomes from databases have been re-analyzed for the presence of endogenous retrovirus integrations. Results suggest that some of the oldest retroviruses, SERV and PcEV, have travelled with their hosts to Asia during the Miocene, when a higher global temperature allowed simian expansions. In contrast, younger viruses, such as SIV and SRV, probably due to the lack of a primate continuum between the continents in later times, have been restricted to Africa and Asia, respectively. Full article

Embryonic stem cells (ESC) have the ability to epigenetically silence endogenous and exogenous retroviral sequences. Trim28 plays an important role in establishing this silencing, but less is known about the role other Trim proteins play. The Tif1 family is a sub-group of the Trim family, which possess histone binding ability in addition to the distinctive RING domain. Here, we have examined the interaction between three Tif1 family members, namely Trim24, Trim28 and Trim33, and their function in retroviral silencing. We identify a complex formed in ESC, comprised of these three proteins. We further show that when Trim33 is depleted, the complex collapses and silencing efficiency of both endogenous and exogenous sequences is reduced. Similar transcriptional activation takes place when Trim24 is depleted. Analysis of the H3K9me3 chromatin modification showed a decrease in this repressive mark, following both Trim24 and Trim33 depletion. As Trim28 is an identified binding partner of the H3K9 methyltransferase ESET, this further supports the involvement of Trim28 in the complex. The results presented here suggest that a complex of Tif1 family members, each of which possesses different specificity and efficiency, contributes to the silencing of retroviral sequences in ESC. Full article

Endogenous retroviruses (ERVs) in mammals are closely related to infectious retroviruses and utilize host tRNAs as a primer for reverse transcription and replication, a hallmark of long terminal repeat (LTR) retroelements. Their dependency on tRNA makes these elements vulnerable to targeting by small RNAs derived from the 3′-end of mature tRNAs (3′-tRFs), which are highly expressed during epigenetic reprogramming and potentially protect many tissues in eukaryotes. Here, we review some key functions of ERV reprogramming during mouse and human development and discuss how small RNA-mediated silencing maintains genome stability when ERVs are temporarily released from heterochromatin repression. In particular, we take a closer look at the tRNA primer binding sites (PBS) of two highly active ERV families in mice and their sequence variation that is shaped by the conflict of successful tRNA priming for replication versus evasion of silencing by 3′-tRFs. Full article

Cancer is a major challenge in our societies, according to the World Health Organization (WHO) about 1/6 deaths were cancer related in 2018 and it is considered the second leading cause of death globally. Immunotherapies have changed the paradigm of oncologic treatment for several cancers where the field had fallen short in providing competent therapies. Despite the improvement, broadly acting and highly effective therapies capable of eliminating or preventing human cancers with insufficient mutated antigens are still missing. Adenoviral vector-based vaccines are a successful tool in the treatment of various diseases including cancer; however, their success has been limited. In this review we discuss the potential of adenovirus as therapeutic tools and the current developments to use them against cancer. More specifically, we examine how to use them to target endogenous retroviruses (ERVs). ERVs, comprising 8% of the human genome, have been detected in several cancers, while they remain silent in healthy tissues. Their low immunogenicity together with their immunosuppressive capacity aid cancer to escape immunosurveillance. In that regard, virus-like-vaccine (VLV) technology, combining adenoviral vectors and virus-like-particles (VLPs), can be ideal to target ERVs and elicit B-cell responses, as well as CD8⁺ and CD4⁺ T-cells responses. Full article

Within the parasitic nematode Ancylostoma ceylanicum, a ~20 million-year-old Bel/Pao LTR retrotransposon encodes an ancient viral class II envelope fusion protein termed Atlas Gc. Typically, retroviruses and related degenerate retrotransposons encode a hemagglutinin-like class I envelope fusion protein. A subset of Bel/Pao LTR retrotransposons within the phylum Nematoda have acquired a phlebovirus-like envelope gene and utilized the encoded fusion machinery to escape the genome as intact exogenous retroviruses. This includes C. elegans retroelement 7 virus which was recently reclassified as a member of the genus Semotivirus. A 3.76 Å cryoEM reconstruction confirms Atlas Gc as a closely related phleboviral homologue and class II fusion protein in a novel case of gene exaptation. Preliminary biophysical and biochemical characterization indicate Atlas Gc functions under specific physiological conditions targeting late-endosomal membranes, much like modern viral class II envelope fusion proteins. Phylogenetic analyses support the reclassification of the Atlas endogenous retrovirus and five other A. ceylanicum ERVs as novel semotiviruses of Belpaoviridae of the new viral order of reverse-transcribing viruses Ortervirales. Full article

A recent study reported the discovery of an endogenous reptilian foamy virus (FV), termed ERV-Spuma-Spu, found in the genome of tuatara. Here, we report two novel reptilian foamy viruses also identified as endogenous FVs (EFVs) in the genomes of panther gecko (ERV-Spuma-Ppi) and Schlegel’s Japanese gecko (ERV-Spuma-Gja). Their presence indicates that FVs are capable of infecting reptiles in addition to mammals, amphibians, and fish. Numerous copies of full length ERV-Spuma-Spu elements were found in the tuatara genome littered with in-frame stop codons and transposable elements, suggesting that they are indeed endogenous and are not functional. ERV-Spuma-Ppi and ERV-Spuma-Gja, on the other hand, consist solely of a foamy virus-like env gene. Examination of host flanking sequences revealed that they are orthologous, and despite being more than 96 million years old, their env reading frames are fully coding competent with evidence for strong purifying selection to maintain expression and for them likely being transcriptionally active. These make them the oldest EFVs discovered thus far and the first documented EFVs that may have been co-opted for potential cellular functions. Phylogenetic analyses revealed a complex virus–host co-evolutionary history and cross-species transmission routes of ancient FVs. Full article