Abstract
Human endogenous retroviruses (HERVs) are abundant sequences that persist within the human genome as remnants of ancient retroviral infections. These sequences became fixed and accumulate mutations or deletions over time. HERVs have affected human evolution and physiology by providing a unique repertoire of coding and non-coding sequences to the genome. In healthy individuals, HERVs participate in immune responses, formation of syncytiotrophoblasts and cell-fate specification. In this Review, we discuss how endogenized retroviral motifs and regulatory sequences have been co-opted into human physiology and how they are tightly regulated. Infections and mutations can derail this regulation, leading to differential HERV expression, which may contribute to pathologies including neurodegeneration, pathological inflammation and oncogenesis. Emerging evidence demonstrates that HERVs are crucial to human health and represent an understudied facet of many diseases, and we therefore argue that investigating their fundamental properties could improve existing therapies and help develop novel therapeutic strategies.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nisole, S. & Saïb, A. Early steps of retrovirus replicative cycle. Retrovirology 1, 9 (2004).
Jern, P. & Coffin, J. M. Effects of retroviruses on host genome function. Annu. Rev. Genet. 42, 709–732 (2008).
de Parseval, N. & Heidmann, T. Human endogenous retroviruses: from infectious elements to human genes. Cytogenet. Genome Res. 110, 318–332 (2005). Together with Jern and Coffin (2008), this paper is a seminal review article that discusses in detail the foundational studies of endogenous retroviruses.
Nurk, S. et al. The complete sequence of a human genome. Science 376, 44–53 (2022).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Vargiu, L. et al. Classification and characterization of human endogenous retroviruses; mosaic forms are common. Retrovirology 13, 7 (2016). This paper is a comprehensive characterization and annotation of the complex HERV structures scattered throughout the human genome.
Chang, Y.-H. & Dubnau, J. Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration. Nat. Commun. 14, 966 (2023).
Dopkins, N. et al. A field guide to endogenous retrovirus regulatory networks. Mol. Cell 82, 3763–3768 (2022).
Yang, B. et al. Species-specific KRAB-ZFPs function as repressors of retroviruses by targeting PBS regions. Proc. Natl Acad. Sci. USA 119, e2119415119 (2022).
Garland, W. et al. Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression. Mol. Cell 82, 1691–1707.e8 (2022).
Bannert, N. & Kurth, R. The evolutionary dynamics of human endogenous retroviral families. Annu. Rev. Genom. Hum. Genet. 7, 149–173 (2006).
Turelli, P. et al. Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements. Genome Res. 24, 1260–1270 (2014).
Groh, S. et al. Morc3 silences endogenous retroviruses by enabling Daxx-mediated histone H3.3 incorporation. Nat. Commun. 12, 5996 (2021).
Chelmicki, T. et al. m6A RNA methylation regulates the fate of endogenous retroviruses. Nature 591, 312–316 (2021).
Girard, A., Sachidanandam, R., Hannon, G. J. & Carmell, M. A. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 442, 199–202 (2006).
Ha, H. et al. A comprehensive analysis of piRNAs from adult human testis and their relationship with genes and mobile elements. BMC Genom. 15, 545 (2014).
Whitelaw, E. & Martin, D. I. K. Retrotransposons as epigenetic mediators of phenotypic variation in mammals. Nat. Genet. 27, 361–365 (2001).
Lu, X. et al. The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat. Struct. Mol. Biol. 21, 423–425 (2014).
Göke, J. et al. Dynamic transcription of distinct classes of endogenous retroviral elements marks specific populations of early human embryonic cells. Cell Stem Cell 16, 135–141 (2015).
Grow, E. J. et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 522, 221–225 (2015).
Barakat, T. S. et al. Functional dissection of the enhancer repertoire in human embryonic stem cells. Cell Stem Cell 23, 276–288.e8 (2018).
He, J. et al. Identifying transposable element expression dynamics and heterogeneity during development at the single-cell level with a processing pipeline scTE. Nat. Commun. 12, 1456 (2021).
She, J. et al. The landscape of hervRNAs transcribed from human endogenous retroviruses across human body sites. Genome Biol. 23, 231 (2022).
Burn, A., Roy, F., Freeman, M. & Coffin, J. M. Widespread expression of the ancient HERV-K (HML-2) provirus group in normal human tissues. PLoS Biol. 20, e3001826 (2022). Together with She et al. (2022), this paper provides an in-depth, locus-specific atlas of HERV RNA expression in various healthy human tissues.
Coffin, J. M. et al. (eds) Retroviruses (Cold Spring Harbor Laboratory, 1997).
Robasky, K., Lewis, N. E. & Church, G. M. The role of replicates for error mitigation in next-generation sequencing. Nat. Rev. Genet. 15, 56–62 (2014).
Treangen, T. J. & Salzberg, S. L. Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat. Rev. Genet. 13, 36–46 (2011).
Berrens, R. V. et al. Locus-specific expression of transposable elements in single cells with CELLO-seq. Nat. Biotechnol. 40, 546–554 (2021). This paper is a cutting-edge bioinformatics pipeline that provides the highest definition of expression of transposable elements from long-read single-cell RNA sequencing.
Troskie, R.-L. et al. Long-read cDNA sequencing identifies functional pseudogenes in the human transcriptome. Genome Biol. 22, 146 (2021).
Lanciano, S. & Cristofari, G. Measuring and interpreting transposable element expression. Nat. Rev. Genet. 21, 721–736 (2020).
Lerat, E. Recent bioinformatic progress to identify epigenetic changes associated to transposable elements. Front. Genet. 13, 891194 (2022).
Rodríguez-Quiroz, R. & Valdebenito-Maturana, B. SoloTE for improved analysis of transposable elements in single-cell RNA-Seq data using locus-specific expression. Commun. Biol. 5, 1063 (2022).
Tokuyama, M. et al. ERVmap analysis reveals genome-wide transcription of human endogenous retroviruses. Proc. Natl Acad. Sci. USA 115, 12565–12572 (2018).
Bendall, M. L. et al. Telescope: characterization of the retrotranscriptome by accurate estimation of transposable element expression. PLoS Comput. Biol. 15, e1006453 (2019).
Yang, W. R., Ardeljan, D., Pacyna, C. N., Payer, L. M. & Burns, K. H. SQuIRE reveals locus-specific regulation of interspersed repeat expression. Nucleic Acids Res. 47, e27 (2019).
Jeong, H.-H., Yalamanchili, H. K., Guo, C., Shulman, J. M. & Liu, Z. in Biocomputing 2018 Vol. 23, 168–179 (World Scientific, 2018).
Smith, C. C. et al. Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma. J. Clin. Invest. 128, 4804–4820 (2018).
Tristem, M. Identification and characterization of novel human endogenous retrovirus families by phylogenetic screening of the human genome mapping project database. J. Virol. 74, 3715–3730 (2000).
Andersson, M. L. et al. Diversity of human endogenous retrovirus class II-like sequences. J. Gen. Virol. 80, 255–260 (1999).
Bao, W., Kojima, K. K. & Kohany, O. Repbase update, a database of repetitive elements in eukaryotic genomes. Mob. DNA 6, 11 (2015).
Paces, J. et al. HERVd: the human endogenous retroviruses database: update. Nucleic Acids Res. 32, D50 (2004).
Becker, J. et al. A comprehensive hybridization model allows whole HERV transcriptome profiling using high density microarray. BMC Genom. 18, 286 (2017).
Garazha, A. et al. New bioinformatic tool for quick identification of functionally relevant endogenous retroviral inserts in human genome. Cell Cycle 14, 1476–1484 (2015).
Hubley, R. et al. The Dfam database of repetitive DNA families. Nucleic Acids Res. 44, D81–D89 (2016).
Xiang, X. et al. Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections. Nat. Commun. 13, 463 (2022).
Kunarso, G. et al. Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat. Genet. 42, 631–634 (2010).
Kigami, D., Minami, N., Takayama, H. & Imai, H. MuERV-L is one of the earliest transcribed genes in mouse one-cell embryos1. Biol. Reprod. 68, 651–654 (2003).
Fueyo, R., Judd, J., Feschotte, C. & Wysocka, J. Roles of transposable elements in the regulation of mammalian transcription. Nat. Rev. Mol. Cell Biol. 23, 481–497 (2022).
Pontis, J. et al. Hominoid-specific transposable elements and KZFPs facilitate human embryonic genome activation and control transcription in naive human ESCs. Cell Stem Cell 24, 724–735.e5 (2019).
Mi, S. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403, 785–789 (2000).
Dupressoir, A. et al. Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene. Proc. Natl Acad. Sci. USA 106, 12127–12132 (2009).
Frank, J. A. et al. Evolution and antiviral activity of a human protein of retroviral origin. Science 378, 422–428 (2022).
Fan, Y. & Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 19, 55–71 (2021).
Dopkins, N. et al. How human endogenous retroviruses interact with the microbiota in health and disease. Trends Microbiol. 30, 812–815 (2022).
Lima-Junior, D. S. et al. Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota. Cell 184, 3794–3811.e19 (2021).
Walsh, D. & Mohr, I. Viral subversion of the host protein synthesis machinery. Nat. Rev. Microbiol. 9, 860–875 (2011).
Mommert, M. et al. Dynamic LTR retrotransposon transcriptome landscape in septic shock patients. Crit. Care 24, 96 (2020).
Dopkins, N. et al. Endogenous reverse transcriptase inhibition attenuates TLR5-mediated inflammation. mBio 14, e0328022 (2023).
Young, G. R., Mavrommatis, B. & Kassiotis, G. Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes. Retrovirology 11, 59 (2014).
Mommert, M. et al. LTR-retrotransposon transcriptome modulation in response to endotoxin-induced stress in PBMCs. BMC Genom. 19, 522 (2018).
Rookhuizen, D. C. et al. Induction transposable element expression is central to innate sensing. Preprint at bioRxiv https://doi.org/10.1101/2021.09.10.457789 (2021).
Yan, N. & Chen, Z. J. Intrinsic antiviral immunity. Nat. Immunol. 13, 214–222 (2012).
Kohli, J., Veenstra, I. & Demaria, M. The struggle of a good friend getting old: cellular senescence in viral responses and therapy. EMBO Rep. 22, e52243 (2021).
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351, 1083–1087 (2016).
Platanitis, E. et al. Interferons reshape the 3D conformation and accessibility of macrophage chromatin. iScience 25, 103840 (2022).
Leung, A. et al. LTRs activated by Epstein–Barr virus-induced transformation of B cells alter the transcriptome. Genome Res. 28, 1791–1798 (2018).
Sutkowski, N., Conrad, B., Thorley-Lawson, D. A. & Huber, B. T. Epstein-Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen. Immunity 15, 579–589 (2001).
Dai, L. et al. Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi’s sarcoma development. Oncogene 37, 4534–4545 (2018).
Toufaily, C., Landry, S., Leib-Mosch, C., Rassart, E. & Barbeau, B. Activation of LTRs from different human endogenous retrovirus (HERV) families by the HTLV-1 tax protein and T-cell activators. Viruses 3, 2146–2159 (2011).
Gonzalez-Hernandez, M. J. et al. Expression of human endogenous retrovirus type K (HML-2) is activated by the Tat protein of HIV-1. J. Virol. 86, 7790–7805 (2012).
O’Carroll, I. P. et al. Structural mimicry drives HIV-1 Rev-mediated HERV-K expression. J. Mol. Biol. 432, 166711 (2020).
Chen, J., Foroozesh, M. & Qin, Z. Transactivation of human endogenous retroviruses by tumor viruses and their functions in virus-associated malignancies. Oncogenesis 8, 6 (2019).
Kyriakou, E. & Magiorkinis, G. Interplay between endogenous and exogenous human retroviruses. Trends Microbiol. 31, 933–946 (2023).
Li, D. & Wu, M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther. 6, 291 (2021).
Anisimova, A. S. et al. Multifaceted deregulation of gene expression and protein synthesis with age. Proc. Natl Acad. Sci. USA 117, 15581–15590 (2020).
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33, 245–254 (2003).
Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl. Med. 7, 307ra153 (2015).
Kassiotis, G. The immunological conundrum of endogenous retroelements. Annu. Rev. Immunol. 41, 99–125 (2023). This paper is a comprehensive overview of the diverse mechanisms by which endogenous retroviruses are involved in immunity.
Liu, X. et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell 186, 287–304.e26 (2023). This study demonstrates that activation of HERV-like particles may contribute to the inflammatory processes that underly ageing-related pathogenesis.
Zhang, H. et al. Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging. Cell Rep. 42, 112593 (2023).
Küry, P. et al. Human endogenous retroviruses in neurological diseases. Trends Mol. Med. 24, 379–394 (2018).
Jansz, N. & Faulkner, G. J. Endogenous retroviruses in the origins and treatment of cancer. Genome Biol. 22, 147 (2021).
Gan, L., Cookson, M. R., Petrucelli, L. & La Spada, A. R. Converging pathways in neurodegeneration, from genetics to mechanisms. Nat. Neurosci. 21, 1300–1309 (2018).
Sun, W., Samimi, H., Gamez, M., Zare, H. & Frost, B. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat. Neurosci. 21, 1038–1048 (2018).
Ramirez, P. et al. Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system. Prog. Neurobiol. 208, 102181 (2022).
Steiner, J. P. et al. Human endogenous retrovirus K envelope in spinal fluid of amyotrophic lateral sclerosis is toxic. Ann. Neurol. 92, 545–561 (2022).
Garcia‐Montojo, M. et al. Antibody response to HML‐2 may be protective in amyotrophic lateral sclerosis. Ann. Neurol. 92, 782–792 (2022).
Viola, M. V., Frazier, M., White, L., Brody, J. & Spiegelman, S. RNA-instructed DNA polymerase activity in a cytoplasmic particulate fraction in brains from Guamanian patients. J. Exp. Med. 142, 483–494 (1975).
Tam, O. H. et al. Postmortem cortex samples identify distinct molecular subtypes of ALS: retrotransposon activation, oxidative stress, and activated glia. Cell Rep. 29, 1164–1177.e5 (2019).
Padmanabhan Nair, V. et al. Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3. Cell Stem Cell 28, 1566–1581.e8 (2021).
Johansson, E. M. et al. Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis. Sci. Adv. 6, eabc0708 (2020).
Jönsson, M. E., Garza, R., Johansson, P. A. & Jakobsson, J. Transposable elements: a common feature of neurodevelopmental and neurodegenerative disorders. Trends Genet. 36, 610–623 (2020).
Jönsson, M. E. et al. Activation of endogenous retroviruses during brain development causes an inflammatory response. EMBO J. 40, e106423 (2021).
Krebs, A.-S. et al. Molecular architecture and conservation of an immature human endogenous retrovirus. Nat. Commun. 14, 5149 (2023).
Douville, R., Liu, J., Rothstein, J. & Nath, A. Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann. Neurol. 69, 141–151 (2011).
Garcia-Montojo, M., Li, W. & Nath, A. Technical considerations in detection of HERV-K in amyotrophic lateral sclerosis: selection of controls and the perils of qPCR. Acta Neuropathol. Commun. 7, 101 (2019).
Mayer, J. et al. Transcriptional profiling of HERV-K(HML-2) in amyotrophic lateral sclerosis and potential implications for expression of HML-2 proteins. Mol. Neurodegener. 13, 39 (2018).
Garson, J. A. et al. Quantitative analysis of human endogenous retrovirus-K transcripts in postmortem premotor cortex fails to confirm elevated expression of HERV-K RNA in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 7, 45 (2019).
Dembny, P. et al. Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors. JCI Insight 5, e131093 (2020).
Guo, C. et al. Tau activates transposable elements in Alzheimer’s disease. Cell Rep. 23, 2874–2880 (2018).
Dawson, T. et al. Locus specific endogenous retroviral expression associated with Alzheimer’s disease. Front. Aging Neurosci. 15, 1186470 (2023).
Pisetsky, D. S. Pathogenesis of autoimmune disease. Nat. Rev. Nephrol. 19, 509–524 (2023).
Perron, H. et al. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. Proc. Natl Acad. Sci. USA 94, 7583–7588 (1997).
Garson, J. A., Tuke, P. W., Giraud, P., Paranhos-Baccala, G. & Perron, H. Detection of virion-associated MSRV-RNA in serum of patients with multiple sclerosis. Lancet 351, 33 (1998).
Nakagawa, K., Brusic, V., McColl, G. & Harrison, L. C. Direct evidence for the expression of multiple endogenous retroviruses in the synovial compartment in rheumatoid arthritis. Arthritis Rheum. 40, 627–638 (1997).
Ogasawara, H. et al. Quantitative analyses of messenger RNA of human endogenous retrovirus in patients with systemic lupus erythematosus. J. Rheumatol. 28, 533–538 (2001).
Treger, R. S. et al. The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV. Immunity 50, 334–347.e9 (2019).
Semsari, H. et al. Association of human endogenous retrovirus-W (HERV-W) copies with pemphigus vulgaris. Curr. Mol. Med. https://doi.org/10.2174/1566524023666230418114152 (2023).
Beck-Engeser, G. B., Eilat, D. & Wabl, M. An autoimmune disease prevented by anti-retroviral drugs. Retrovirology 8, 91 (2011).
Rice, G. I. et al. Reverse-transcriptase inhibitors in the Aicardi–Goutières syndrome. N. Engl. J. Med. 379, 2275–2277 (2018).
Hartung, H.-P. et al. Efficacy and safety of temelimab in multiple sclerosis: results of a randomized phase 2b and extension study. Mult. Scler. 28, 429–440 (2022).
Rajurkar, M. et al. Reverse transcriptase inhibition disrupts repeat element life cycle in colorectal cancer. Cancer Discov. 12, 1462–1481 (2022).
Ukadike, K. C. et al. Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus. Mob. DNA 14, 5 (2023).
Bach, J.-F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).
Wu, S., Zhu, W., Thompson, P. & Hannun, Y. A. Evaluating intrinsic and non-intrinsic cancer risk factors. Nat. Commun. 9, 3490 (2018).
Reid Cahn, A., Bhardwaj, N. & Vabret, N. Dark genome, bright ideas: recent approaches to harness transposable elements in immunotherapies. Cancer Cell 40, 792–797 (2022).
Babaian, A. & Mager, D. L. Endogenous retroviral promoter exaptation in human cancer. Mob. DNA 7, 24 (2016).
Babaian, A. et al. Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma. Oncogene 35, 2542–2546 (2016).
Lamprecht, B. et al. Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat. Med. 16, 571–579 (2010).
Wiesner, T. et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature 526, 453–457 (2015).
Scarfò, I. et al. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. Blood 127, 221–232 (2016).
Lock, F. E. et al. Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 111, E3534–E3543 (2014).
Liu, A. Y. & Abraham, B. A. Subtractive cloning of a hybrid human endogenous retrovirus and calbindin gene in the prostate cell line PC3. Cancer Res. 51, 4107–4110 (1991).
Attig, J. et al. Human endogenous retrovirus onco-exaptation counters cancer cell senescence through calbindin. J. Clin. Invest. 133, e164397 (2023).
Singh, B. et al. Locus specific human endogenous retroviruses reveal new lymphoma subtypes. Preprint at bioRxiv https://doi.org/10.1101/2023.06.08.544208 (2023).
Steiner, M. C. et al. Locus-specific characterization of human endogenous retrovirus expression in prostate, breast, and colon cancers. Cancer Res. 81, 3449–3460 (2021).
Alcazer, V. et al. HERVs characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy. Am. J. Hematol. 97, 1200–1214 (2022).
Ng, K. W. et al. Antibodies against endogenous retroviruses promote lung cancer immunotherapy. Nature 616, 563–573 (2023). This study demonstrates the possibly tumourigenic effects of HERV protein expression and its immunotherapeutic potential.
Saini, S. K. et al. Human endogenous retroviruses form a reservoir of T cell targets in hematological cancers. Nat. Commun. 11, 5660 (2020).
Bonaventura, P. et al. Identification of shared tumor epitopes from endogenous retroviruses inducing high-avidity cytotoxic T cells for cancer immunotherapy. Sci. Adv. 8, eabj3671 (2022).
Burbage, M. et al. Epigenetically controlled tumor antigens derived from splice junctions between exons and transposable elements. Sci. Immunol. 8, eabm6360 (2023).
Merlotti, A. et al. Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer. Sci. Immunol. 8, eabm6359 (2023). This study provides a molecular basis for the selection of endogenous retroviruses that can form recurrent neoantigens in various malignancies.
Cuevas, M. V. R. et al. BamQuery: a proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens. Genome Biol. 24, 188 (2023).
Ehx, G. et al. Atypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes. Immunity 54, 737–752.e10 (2021).
Shah, N. M. et al. Pan-cancer analysis identifies tumor-specific antigens derived from transposable elements. Nat. Genet. 55, 631–639 (2023).
Wang, E. & Aifantis, I. RNA splicing and cancer. Trends Cancer 6, 631–644 (2020).
Ko, E.-J. et al. Expression profiles of human endogenous retrovirus (HERV)-K and HERV-R Env proteins in various cancers. BMB Rep. 54, 368–373 (2021).
Shah, A. H. et al. Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma. J. Clin. Invest. 133, e167929 (2023).
Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).
Marofi, F. et al. CAR T cells in solid tumors: challenges and opportunities. Stem Cell Res. Ther. 12, 81 (2021).
Smith, C. C. et al. Alternative tumour-specific antigens. Nat. Rev. Cancer 19, 465–478 (2019).
Wang-Johanning, F. et al. Immunotherapeutic potential of anti-human endogenous retrovirus-K envelope protein antibodies in targeting breast tumors. J. Natl Cancer Inst. 104, 189–210 (2012).
Zhou, F. et al. Chimeric antigen receptor T cells targeting HERV-K inhibit breast cancer and its metastasis through downregulation of Ras. Oncoimmunology 4, e1047582 (2015).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Molecular Cell Biology thanks Stéphane Depil, Paola Bonaventura and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Dysbiosis
-
The state of disbalance in the composition and diversity of microorganisms that constitute the microbiota of a host organism.
- Expectation–maximization
-
An algorithmic computational approach that iteratively defines the maximum likelihood for given estimations based on latent variables, commonly used to improve upon estimations provided by probabilistic models of data.
- Inflammasome
-
Multisubunit complex that assemble in the cytosol in response to inflammatory stimuli. Following their assembly, inflammasomes transduce immunological signals.
- Inflammatory disorders
-
Conditions in which unregulated and typically self-targeting inflammation contributes to pathogenesis. Inflammatory disorders generally demonstrate cyclic cascades of immune responses that further reinforce incipient inflammation.
- Neurofibrillary tangles
-
Pathological insoluble aggregates of hyperphosphorylated tau protein in the central nervous system.
- Pattern recognition receptors
-
Invariant innate immunity receptors that recognize and detect molecular signals that commonly arise from pathogen invasion or cellular damage.
- Retrovirus-like particles
-
Assembled endogenous retroviral particles that are morphologically similar to an infectious retrovirus but are replication incompetent and thus non-infectious.
- Superantigen
-
Molecules that possess nonspecific stimulatory capacity of adaptive immunity cell subsets.
- Syncytiotrophoblast
-
A barrier layer of multinucleated epithelial cells that separates the maternal and embryonic circulatory systems.
- Ty3 or mdg4
-
A phylogeny of LTR-possessing retroelements. The previously used nomenclature for these elements relied on the word ‘gypsy’; going forward, these elements should be referred to as ‘Ty3’ or ‘mdg4’.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Dopkins, N., Nixon, D.F. Activation of human endogenous retroviruses and its physiological consequences. Nat Rev Mol Cell Biol 25, 212–222 (2024). https://doi.org/10.1038/s41580-023-00674-z
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41580-023-00674-z
This article is cited by
-
Ribosomal profiling of human endogenous retroviruses in healthy tissues
BMC Genomics (2024)