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Results for “endogenous viral elements”

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PubMed2025

HI-FEVER: a Nextflow pipeline for the high-throughput discovery and annotation of endogenous viral elements.

SUMMARY: Endogenous viral elements (EVEs) offer valuable insights into virus and host evolution, but their detection remains computationally and biologically challenging. We present HI-FEVER, a user-friendly Nextflow pipeline for the discovery of EVEs in eukaryotic host genomes. HI-FEVER is highly parallelizable and customizable, ensuring computational efficiency while allowing researchers to fine-tune parameters to their specific needs. Its output provides a comprehensive analysis of discovered EVEs, including detailed annotations which can provide evolutionary insights. HI-FEVER scales seamlessly to handle millions of viral protein queries across multiple host genomes on both laptops and high-performance computing nodes. AVAILABILITY AND IMPLEMENTATION: The HI-FEVER source code is available on GitHub at https://github.com/PaleovirologyLab/hi-fever. Minimal reference databases, test datasets and benchmarking results are hosted on the Open Science Framework at https://osf.io/y357r. A detailed wiki is available at https://github.com/PaleovirologyLab/hi-fever/wiki, including usage instructions, parameter descriptions, and guidance on interpreting outputs. The pipeline includes a Pixi environment compatible with Conda and Apptainer containerization, and Docker images. HI-FEVER has been tested on Linux, Windows (via WSL2), and macOS (Intel and ARM64).

Software↗

PubMed2026

MDV-like endogenous viral elements act as immune rheostats in Aedes cells by modulating defensin A-mediated responses to arboviruses.

Mosquito cell lines are essential tools for arbovirus research. Endogenous viral elements (EVEs) are prevalent in mosquito genomes, yet their functional effects on host immune responses remain unclear, potentially complicating experimental interpretations. In this study, we systematically characterized endogenous mosquito densovirus-like elements (EMLs) within the Aedes aegypti Aag2 cell line and found that these endogenous EMLs are transcriptionally active but translationally defective. The silencing of EML transcripts significantly diminished the replication of Zika virus (ZIKV), Japanese encephalitis virus (JEV), and chikungunya virus (CHIKV), while transiently increasing dengue virus 2 (DENV-2), thereby indicating a virus-dependent regulatory mechanism. Mechanistically, RNA sequencing after EML interference, alongside plasmid-based mimic expression, demonstrated that EML transcripts downregulate defensin A, an antimicrobial peptide produced by mosquitoes. Functional assays using synthetic defensin A showed that this peptide differentially regulates arboviral infection. Binding assays and structural modeling further supported its interaction with viral envelope proteins, while stage-restricted infection assays revealed distinct stages of action: defensin A enhanced adsorption of ZIKV, JEV, and CHIKV, but did not promote DENV-2 adsorption or entry, and instead reduced DENV-2 RNA accumulation at the post-entry replication stage. Our findings highlight a previously unrecognized role of densovirus-derived EVEs in mosquito innate immunity, extending their functional scope from the well-established PIWI-interacting RNA-mediated antiviral defense to the regulation of antimicrobial peptide-associated immune pathways. These findings emphasize the necessity of accounting for EVE activity when analyzing data derived from mosquito cell lines, and suggest that related EVE-mediated immune regulation may contribute to arbovirus dynamics in mosquitoes.IMPORTANCEMosquito-borne viruses such as dengue, Zika, Japanese encephalitis, and chikungunya continue to threaten human health worldwide. Laboratory studies often use Aedes aegypti cell lines to investigate how these viruses interact with their mosquito hosts. Here, we show that the genomes of these cells contain endogenous viral elements derived from mosquito densoviruses. Far from being inert fossils, these sequences are transcriptionally active and regulate mosquito immunity by suppressing the antimicrobial peptide defensin A. This immune modulation influences the replication of different arboviruses in opposite ways, enhancing some while restricting others. Our findings reveal that integrated viral elements can shape the outcome of arbovirus infection, with important implications for interpreting mosquito cell culture experiments and for evaluating endogenous viral element-mediated immune regulation in mosquito-virus interactions.

Aag2 cell↗

PubMed2025

Dating the origin of a viral domestication event in parasitoid wasps attacking Diptera.

Over the course of evolution, hymenopteran parasitoids have developed a close relationship with heritable viruses, sometimes integrating viral genes into their chromosomes. For example, in Drosophila parasitoids belonging to the Leptopilina genus, 13 viral genes from the Filamentoviridae family have been domesticated to deliver immunosuppressive factors to host immune cells, thereby protecting parasitoid offspring from the host immune response. The present study aims to comprehensively characterize this domestication event in terms of the viral genes involved, the wasp diversity affected by this event and its chronology. Our genomic analysis of 41 Cynipoidea wasps from six subfamilies revealed 18 viral genes that were endogenized during the early radiation of the Eucoilini/Trichoplastini clade around 75 million years ago. Wasps from this highly diverse clade develop not only from Drosophila but also from a variety of Schizophora. This event coincides with the radiation of Schizophora, a highly speciose Diptera clade, suggesting that viral domestication facilitated wasp diversification in response to host diversification. Additionally, in one of the species, at least one viral gene was replaced by another gene derived from a related filamentovirus. This study highlights the impact of viral domestication on the diversification of parasitoid wasps.

Animals↗

PubMed2026

A G-Quadruplex-Activated Near-Infrared Chemiluminescent Probe for In Situ Hepatic Imaging of the Hepatitis C Virus Genome.

Real-time monitoring of viral replication is essential for infectious disease diagnosis and antiviral drug development. The G-quadruplex (G4), a conserved regulatory element within viral genomes, represents a significant endogenous biomarker for tracking viral activity. However, imaging viral G4s in deep tissues remains a challenge for current optical technologies due to severe photon attenuation and autofluorescence. Herein, we report Lumin680, the first near-infrared (NIR) chemiluminescent probe directly activated by conserved viral G4 conformations. Its chemiluminescence was triggered by parallel G4, emitting in the NIR optical window (680 nm) with a 104.6-fold signal enhancement. Notably, the luminescence of Lumin680 could penetrate up to 1.2 cm of biological tissue, outperforming traditional G4 fluorescent probe. In vivo, Lumin680 enabled the rapid visualization of orthotopic hepatitis C virus (HCV) genome RNA-presenting mini-organ within 5 min post-intravenous administration. Furthermore, the chemiluminescent intensity of Lumin680 quantitatively mapped the therapeutic efficacy of clinical direct-acting antivirals (DAAs) at both the cellular and whole-animal levels, exhibiting high concordance with the gold-standard quantitative RT-PCR (qPCR). This study not only provides a powerful G4 specific chemiluminescent tool but also establishes a novel paradigm for the non-invasive, in situ diagnosis and precise therapeutic monitoring of viral infections.

G-Quadruplexes↗

PubMed1978

Linkage of the endogenous avian leukosis virus genome of virus-producing chicken cells to inhibitory cellular DNA sequences.

The endogenous avian leukosis virus genome of uninfected virus-producing(V+) chicken embryo fibroblasts appears to be inefficiently transcribed and is noninfectious in transfection assays of high molecular weight DNA. We previously proposed that the endogenous virus genome was linked to a cis-acting control element which inhibited its transcription and, consequently, interfered with transfection by endogenous viral DNA. We now report that DNA of uninfected V+ cells is infectious at a low level when sheared to the approximate size of the virus genome. These results suggest that the endogenous virus genome of uninfected V+ chicken cells can be converted to an infectious form by separating it from adjacent cellular DNA sequences, as predicted by the cis-acting control element model.

Animals↗

PubMed1978

Purification and characterization of particles containing RNA-dependent DNA polymerase, in the allantoic fluid of uninfected leukosis virus-free chicken eggs.

The allantoic fluid of embryonated chicken eggs regularly contains particle-associated RNA-dependent DNA polymerase, as shown by its reaction with homopolymeric and heteropolymeric RNA and by the characterization of the products. The purification of the particles is described. The purified particles are different from the known avian RNA tumor viruses in their protein composition and their sedimentation constant. They do not exhibit biological properties typical for RNA tumour viruses, such as helper activity, interfering properties or infectivity and do not show endogenous DNA synthesis. The particles are discussed as non-viral elements.

Allantois↗

PubMed2026

Viral mimicry escape as a necessary feature of malignant transformation.

Malignant transformation is driven by disruption of pathways regulating proliferation and cell fate, but these same disruptions can create a collateral vulnerability: loss of transcriptional and epigenetic control over transposable elements and other normally silenced genomic regions. Consequently, emerging cancer cells can accumulate transposable element-derived and other endogenous immunogenic nucleic acids capable of triggering antiviral responses, a process termed viral mimicry. Increasing evidence indicates that viral mimicry can eliminate precancerous cells and shape tumour evolution, positioning it as an intrinsic tumour-suppressive mechanism. Here we highlight how cancer-associated changes in DNA methylation, histone modifications, splicing and RNA processing can lead to the presence of immunogenic nucleic acids that can activate viral mimicry pathways. We outline how cancer cells suppress viral mimicry, including compensatory epigenetic repression, RNA editing, nucleic acid decay and dampening of interferon signalling to enable cancer cell growth. Finally, we highlight the evidence suggesting that escaping viral mimicry is a fundamental process for cancer initiation and progression, and suggest that viral mimicry escape is necessary for cancer transformation and a therapeutic target in combination with immunotherapies. By framing viral mimicry escape as a necessary part of cancer transformation, this Review provides a unifying conceptual model for its translational exploitation.

Journal Article↗

PubMed1977

Rauscher-leukemia-virus-related sequences in human DNA: presence in some tissues of some patients with hemotopoietic neoplasias and absence in DNA from other tissues.

A [3H[cDNA probe synthesized from the RNA genome of Rauscher murine leukemia virus (MuLVR) and purified by hybridization to MuLVR70S RNA was hybridized to DNA from human normal and hemotopoietic neoplasia tissues. This cDNA hybridized completely to its homologous 70S RNA and was free of self-complementary sequences. Sequences complementary to MuLVR cDNA were found in DNA from tissues of some patients with leukemia (2 of 8), Hodgkin's disease (3 of 10), and one patient with multiple myeloma. DNA from spleen and kidney of a patient with nonneoplastic disease did not contain detectable MuLVR-related sequences. These virus-related sequences in the DNA from these neoplastic tissues were related but not identical to MuLVR sequences because differences of approximately 6 degrees in the midpoints of thermal elution profiles were found between the heterologous and homologous duplexes. These nucleotide sequences are not the same as the proviral sequences of baboon type-C virus previously found from some other patients with leukemia [Reitz et al. (1976) Proc. Natl. Acad. Sci. USA 73,2113-2117; Wong-Staal et al. (1976) Nature 262, 190-195], because there is no sequence homology between nucleic acids from MuLVR and baboon virus. The absence of these nucleic acid sequences in many tissues of patients with neoplasia and from the few tissues examined from people with nonneoplastic disease suggests that they are not endogenous elements but are acquired after fertilization. Taken together with the previous detection of baboon and woolly monkey type-C viral related components in some human tumors, the results suggest acquisition of at least three types of type-C viral sequences in the human population.

Base Sequence↗

PubMed2025

Evolution of antiviral host defenses against a backdrop of endogenous retroelements.

Mammalian hosts deploy a multitude of germ line-encoded mechanisms to detect and restrict virus infection. These mechanisms must avoid pathological responses to endogenous retroviruses and other endogenous retrotransposable elements (RTEs)-viruses and viruslike genomic parasites that have invaded the host germ line and are passed down the generations as host genes. Although the location, specificity, and sensitivity of innate pattern recognition receptors and restriction factors are tuned to facilitate discrimination of infecting viruses from those that are part of self, immune cross-reactions do occur. The RTE viral heritage may, therefore, compromise the ability of the host to respond to virus infection without risking pathology. Nevertheless, RTEs have the potential to be co-opted as an alarm amplification system, to be repurposed as antiviral factors, and to contribute to the evolution of antiviral genes.

Animals↗

PubMed2026

Human endogenous retroviruses leading to autoimmune diseases.

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and were long regarded as inert remnants of ancestral retroviral infections. Increasing evidence indicates that HERVs are active genomic elements capable of influencing transcriptional programs, modulating immune responses, and contributing to disease pathogenesis. Under physiological conditions, HERV expression is tightly controlled by epigenetic mechanisms; however, infections, chronic inflammation, aging, and diverse environmental stimuli can promote HERV reactivation. HERV-derived RNAs and proteins engage innate immune sensors and trigger antiviral-like responses through mechanisms of viral mimicry, leading to activation of type I interferon and other inflammatory pathways. HERV dysregulation has been associated with disease-relevant immune pathways. This review summarizes recent advances linking HERVs to autoimmune disease pathogenesis and discusses their potential translational relevance as biomarkers and therapeutic targets.

Humans↗

PubMed1979

Endogenous mammary tumour virus DNA varies among wild mice and segregates during inbreeding.

Proviruses of the mouse mammary tumour virus (MMTV) endogenous to normal mice can be identified by molecular hybridisation and distinguished using restriction endonucleases. Feral mice display marked heterogeneity with respect to the number of copies and the sites of insertion of endogenous MMTV-specific DNA, with occasional mice apparently free of MMTV DNA. Several different MMTV proviruses present in laboratory mice have segregated like stable, independent genetic elements during the inbreeding which followed a cross between Bagg albino and DBA mice 60 years ago. The results favour the hypothesis that endogenous proviruses have been established by multiple, independent infections of germ cells rather than by somatic mutation of ancestral proviruses or of cellular genes.

Animals↗

PubMed1979

Formation of Rous associated virus-60: origin of the polymerase gene.

The DNA of normal chicken embryos contains sequences related to the avian leukosis-sarcoma viruses. RNA-dependent DNA polymerase of these viruses is encoded by a genetic element known as the pol gene. The nature of the endogenous virus pol gene in chicken cells was investigated by testing its ability to participate in genetic recombination. Rous-associated virus-60-type recombinant viruses isolated after infection of chicken cells with strains tsLA337PR-B or tsNY21SR-A, both of which produce a temperature-sensitive DNA polymerase, also possessed the temperature-sensitive lesion. These results are consistent with the hypothesis that the endogenous viral information used for the generation of Rous-associated virus-60 is deficient in at least part of the pol gene and that the defect includes that portion represented by the lesions in NY21 and LA337. The frequency of polymerase-negative BH-Rous sarcoma virus alpha formation was not affected by the levels of endogenous viral expression, which suggests that the alpha defect is not derived from the endogenous pol gene.

Animals↗

PubMed1977

Divergence of baboon endogenous type C virogenes in primates: genomic viral RNA in molecular hybridization experiments.

RNA purified from two related RNA tumor viruses, one isolated from a baboon, Papio anubis, and the second from cultured blood leukocytes of a patient with acute myelogenous leukemia, was labeled with 125I and hybridized to DNA from different primates. RNA from both viruses showed maximum sequence homology with genes in baboons and little homology with genes of humans. The results confirm earlier suggestions that both viruses originated by transcription of baboon virogenes, and that one was transmitted to humans in nature. Hybridization of the viral RNA to cell DNA followed complicated kinetic patterns, indicating the presence of both repeated and infrequent virogene elements. This conclusion was verified in experiments using varied DNA:RNA ratios. It is proposed that virogenes, though composed of genes repeated 10 times or more, consist of some sequences more preferentially conserved than others. The non-uniformity of virogene sequence conservation limits the use of viral probes in studies concerning certain aspects of virogene evolution.

Animals↗

PubMed1978

Why cell biologists should be aware of genetically transmitted viruses.

Retrovirus genomes exist as endogenous genetic elements in the cells of many species used in biomedical research. Many cell lines spontaneously release virus, and other cells are induced to do so by procedures commonly used in research laboratories. The expression of endogenous retroviruses can affect the results of seemingly unrelated experiments. Some retroviruses endogenous to animals grow avidly in human cells. They are not known to be hazardous to man, but further studies are necessary.

Animals↗

PubMed1977

Continuous tissue culture cell lines derived from chemically induced tumors of Japanese quail.

Several continuous tissue culture cell lines were established from methylcholanthrene-induced fibrosarcomas of Japanese quail. The lines consist either of fibroblastic elements, round refractile cells or polygonal cells. They show transformed characteristics in agar colony formation and hexose uptake, and most are tumorigenic. Their cloning efficiency in plastic dishes is not increased over that of normal quail embryo fibroblasts. The quail tumor cell lines do not produce endogenous avian oncoviruses and fail to complement the Bryan high titer strain of Rous sarcoma virus; those tested lack the p27 protein of avian oncoviruses. Most of the cell lines are susceptible to subgroup A avian sarcoma viruses, but are relatively resistant to viruses of subgroups C, E and F as compared to normal quail embryo fibroblasts.

Alpharetrovirus↗

PubMed2026

An ancient alpharetrovirus lineage in bats: Evolutionary insights and possible roles in reproduction.

Alpharetroviruses are an important group of pathogens known to cause leukemias and tumors, and were historically considered to be restricted to avian hosts. The identification of alpharetrovirus-like envelopes in bat genomes has hinted at a potentially wider host range, although their relations to modern alpharetroviruses and distribution remains unclear. Through a paleovirological screening of 818 vertebrate genomes we identified CHIRalphaEnv, a lineage that belongs firmly within alpharetroviruses, and emerged from a cross-class transmission from saurian hosts. We determine that CHIRalphaEnv envelope genes have been co-opted across bats on eight separate occasions between 43.8 and 18.9 million years ago and are preserved in most bat genomes screened. CHIRalphaEnv elements encode full-length envelope proteins and have been maintained under purifying selection, demonstrating multiple instances of exaptation by their bat hosts and a likely ubiquitous function. We observe high expression levels of CHIRalphaEnv envelopes in endometrium tissue from Carollia perspicillata, suggesting an involvement in reproductive function. We find CHIRalphaEnv sequence relatives in multiple mammalian clades (Afrotherians, rodents and bats), expanding the host range and extending origins of alpharetroviruses beyond 43 million years. We also propose the first mammalian co-opted Endogenous retrovirus (ERV) derived from an Alpharetrovirus envelope and explore the convergent functional recruitment of CHIRalphaEnv in hemochorial placentation in bats, elephant shrews and spiny mice. These findings highlight alpharetroviruses as a previously underappreciated source of functional exaptation in mammals.

Animals↗