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  • Review Article
  • Published:

Immune responses to endogenous retroelements: taking the bad with the good

Key Points

  • Vertebrate genomes host a vast number of endogenous retroelements that exhibit distinct genomic structure, open reading frame integrity and replication autonomy or capability.

  • Certain endogenous retroelement features have been retained to serve important immunological and non-immunological functions in the host. However, retention of 'viral' characteristics renders endogenous retroelements immunogenic.

  • Despite targeted epigenetic silencing, many endogenous retroelements are still transcribed in adult cells and tissues. Such expression is strongly modulated in immune cells, particularly by immune stimuli.

  • Endogenous retroelement-derived nucleic acids activate innate immune pathways, which contributes to pathologies such as systemic lupus erythematosus and Aicardi–Goutières syndrome. It also enhances responses to poorly immunogenic antigens, such as T cell-independent type 2 antigens or tumours.

  • T cell and B cell responses to endogenous retroelement proteins are frequently detected. These adaptive responses contribute to the development of autoimmunity, but they can also lead to the targeting of abnormal cells, such as tumour cells, for destruction.

  • Induction of endogenous retroelements by commensal colonization, pathogenic infection or cellular transformation may have evolved as an intrinsic warning system. Such beneficial contributions of immune reactivity to endogenous retroelements balance their pathogenic potential.

Abstract

The ultimate form of parasitism and evasion of host immunity is for the parasite genome to enter the germ line of the host species. Retroviruses have invaded the host germ line on the grandest scale, and this is evident in the extraordinary abundance of endogenous retroelements in the genome of all vertebrate species that have been studied. Many of these endogenous retroelements have retained viral characteristics; some also the capacity to replicate and, consequently, the potential to trigger host innate and adaptive immune responses. However, although retroelements are mainly recognized for their pathogenic potential, recent evidence suggests that this 'enemy within' may also have beneficial roles in tuning host immune reactivity. In this Review, we discuss how the immune system recognizes and is shaped by endogenous retroelements.

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Figure 1: Topology of endogenous retroelement nucleic acid replication and sensors.
Figure 2: Transcriptional induction of endogenous retroelements in immune cells.
Figure 3: Context-dependent immune reactivity to endogenous retroelements.

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References

  1. Cohn, M. The immune system: a weapon of mass destruction invented by evolution to even the odds during the war of the DNAs. Immunol. Rev. 185, 24–38 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hedrick, S. M. The acquired immune system: a vantage from beneath. Immunity 21, 607–615 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Dewannieux, M. & Heidmann, T. Endogenous retroviruses: acquisition, amplification and taming of genome invaders. Curr. Opin. Virol. 3, 646–656 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Feschotte, C. & Gilbert, C. Endogenous viruses: insights into viral evolution and impact on host biology. Nat. Rev. Genet. 13, 283–296 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Stoye, J. P. Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat. Rev. Microbiol. 10, 395–406 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Maksakova, I. A. et al. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet. 2, e2 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stocking, C. & Kozak, C. A. Murine endogenous retroviruses. Cell. Mol. Life Sci. 65, 3383–3398 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cordaux, R. & Batzer, M. A. The impact of retrotransposons on human genome evolution. Nat. Rev. Genet. 10, 691–703 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jern, P. & Coffin, J. M. Effects of retroviruses on host genome function. Annu. Rev. Genet. 42, 709–732 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Dupressoir, A., Lavialle, C. & Heidmann, T. From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation. Placenta 33, 663–671 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Benit, L., Dessen, P. & Heidmann, T. Identification, phylogeny, and evolution of retroviral elements based on their envelope genes. J. Virol. 75, 11709–11719 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Villesen, P., Aagaard, L., Wiuf, C. & Pedersen, F. S. Identification of endogenous retroviral reading frames in the human genome. Retrovirology 1, 32 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. de Parseval, N., Lazar, V., Casella, J. F., Benit, L. & Heidmann, T. Survey of human genes of retroviral origin: identification and transcriptome of the genes with coding capacity for complete envelope proteins. J. Virol. 77, 10414–10422 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Subramanian, R. P., Wildschutte, J. H., Russo, C. & Coffin, J. M. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8, 90 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dewannieux, M. et al. Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements. Genome Res. 16, 1548–1556 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee, Y. N. & Bieniasz, P. D. Reconstitution of an infectious human endogenous retrovirus. PLoS Pathog. 3, e10 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Maksakova, I. A., Mager, D. L. & Reiss, D. Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cell. Mol. Life Sci. 65, 3329–3347 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Rowe, H. M. & Trono, D. Dynamic control of endogenous retroviruses during development. Virology 411, 273–287 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Balada, E., Ordi-Ros, J. & Vilardell-Tarres, M. Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity. Rev. Med. Virol. 19, 273–286 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Baudino, L., Yoshinobu, K., Morito, N., Santiago-Raber, M. L. & Izui, S. Role of endogenous retroviruses in murine SLE. Autoimmun. Rev. 10, 27–34 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Hancks, D. C. & Kazazian, H. H. Jr. Active human retrotransposons: variation and disease. Curr. Opin. Genet. Dev. 22, 191–203 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kassiotis, G. Endogenous retroviruses and the development of cancer. J. Immunol. 192, 1343–1349 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Perl, A., Fernandez, D., Telarico, T. & Phillips, P. E. Endogenous retroviral pathogenesis in lupus. Curr. Opin. Rheumatol. 22, 483–492 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ruprecht, K., Mayer, J., Sauter, M., Roemer, K. & Mueller-Lantzsch, N. Endogenous retroviruses and cancer. Cell. Mol. Life Sci. 65, 3366–3382 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Volkman, H. E. & Stetson, D. B. The enemy within: endogenous retroelements and autoimmune disease. Nat. Immunol. 15, 415–422 (2014). This is an exceptional review of the findings implicating innate recognition of endogenous retroelements in the pathogenesis of AGS and SLE.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Eickbush, T. H. & Jamburuthugoda, V. K. The diversity of retrotransposons and the properties of their reverse transcriptases. Virus Res. 134, 221–234 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Xiong, Y. & Eickbush, T. H. Origin and evolution of retroelements based upon their reverse transcriptase sequences. EMBO J. 9, 3353–3362 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Richardson, S. R. et al. The influence of LINE-1 and SINE retrotransposons on mammalian genomes. Microbiol. Spectr. 3, MDNA3–0061–2014 (2015).

    PubMed  Google Scholar 

  29. Brouha, B. et al. Hot L1s account for the bulk of retrotransposition in the human population. Proc. Natl Acad. Sci. USA 100, 5280–5285 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Burns, K. H. & Boeke, J. D. Human transposon tectonics. Cell 149, 740–752 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Goodier, J. L. & Kazazian, H. H. Jr. Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135, 23–35 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Richardson, S. R., Morell, S. & Faulkner, G. J. L1 retrotransposons and somatic mosaicism in the brain. Annu. Rev. Genet. 48, 1–27 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Lee, E. et al. Landscape of somatic retrotransposition in human cancers. Science 337, 967–971 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ahl, V., Keller, H., Schmidt, S. & Weichenrieder, O. Retrotransposition and crystal structure of an Alu RNP in the ribosome-stalling conformation. Mol. Cell 60, 715–727 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Shimizu, A. et al. Characterisation of cytoplasmic DNA complementary to non-retroviral RNA viruses in human cells. Sci. Rep. 4, 5074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McCarthy, E. M. & McDonald, J. F. Long terminal repeat retrotransposons of Mus musculus. Genome Biol. 5, R14 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Stoye, J. P. & Moroni, C. Phenotypic mixing of retroviruses in mitogen-stimulated lymphocytes: analysis of xenotropic and defective endogenous mouse viruses. J. Gen. Virol. 65, 317–326 (1984).

    Article  PubMed  Google Scholar 

  38. Contreras-Galindo, R. et al. Human endogenous retrovirus type K (HERV-K) particles package and transmit HERV-K-related sequences. J. Virol. 89, 7187–7201 (2015). This is an intriguing study highlighting the potential of defective HERV-K proviruses to form transducing viral particles in human cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Young, G. R. et al. Resurrection of endogenous retroviruses in antibody-deficient mice. Nature 491, 774–778 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yu, P. et al. Nucleic acid-sensing Toll-like receptors are essential for the control of endogenous retrovirus viremia and ERV-induced tumors. Immunity 37, 867–879 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Magiorkinis, G., Gifford, R. J., Katzourakis, A., De, R. J. & Belshaw, R. Env-less endogenous retroviruses are genomic superspreaders. Proc. Natl Acad. Sci. USA 109, 7385–7390 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Young, G. R., Mavrommatis, B. & Kassiotis, G. Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes. Retrovirology 11, 59 (2014). This is the first study to show genome-wide modulation of endogenous retroelement expression by exposure to pathogenic and commensal microorganisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jirtle, R. L. & Skinner, M. K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 8, 253–262 (2007). This is an outstanding review that focuses on the links between environmental cues and alterations in gene and endogenous retroelement expression that lead to disease phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roman, A. C., Benitez, D. A., Carvajal-Gonzalez, J. M. & Fernandez-Salguero, P. M. Genome-wide B1 retrotransposon binds the transcription factors dioxin receptor and Slug and regulates gene expression in vivo. Proc. Natl Acad. Sci. USA 105, 1632–1637 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Okudaira, N. et al. Induction of long interspersed nucleotide element-1 (L1) retrotransposition by 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct. Proc. Natl Acad. Sci. USA 107, 18487–18492 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Okudaira, N. et al. Long interspersed element-1 is differentially regulated by food-borne carcinogens via the aryl hydrocarbon receptor. Oncogene 32, 4903–4912 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Moroni, C. et al. Normal B-cell activation involves endogenous retroviral antigen expression: implications for leukemogenesis. Cold Spring Harb. Symp. Quant. Biol. 44, 1205–1210 (1980).

    Article  CAS  PubMed  Google Scholar 

  48. Stoye, J. P. & Moroni, C. Endogenous retrovirus expression in stimulated murine lymphocytes. Identification of a new locus controlling mitogen induction of a defective virus. J. Exp. Med. 157, 1660–1674 (1983).

    Article  CAS  PubMed  Google Scholar 

  49. Collins, P. L., Kyle, K. E., Egawa, T., Shinkai, Y. & Oltz, E. M. The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes. Proc. Natl Acad. Sci. USA 112, 8367–8372 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zeng, M. et al. MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Science 346, 1486–1492 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hung, T. et al. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science 350, 455–459 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Barbalat, R., Ewald, S. E., Mouchess, M. L. & Barton, G. M. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Pisitkun, P. et al. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669–1672 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Subramanian, S. et al. A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc. Natl Acad. Sci. USA 103, 9970–9975 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Santiago-Raber, M. L., Baudino, L. & Izui, S. Emerging roles of TLR7 and TLR9 in murine SLE. J. Autoimmun. 33, 231–238 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015). References 57 and 58 reveal the contribution of innate recognition of transcriptionally induced endogenous retroelements in the therapeutic response of human cancers to azacitidine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Crow, Y. J. & Rehwinkel, J. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum. Mol. Genet. 18, R130–R136 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rice, G. I. et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46, 503–509 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhao, K. et al. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutieres syndrome-related SAMHD1. Cell Rep. 4, 1108–1115 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Goodier, J. L., Cheung, L. E. & Kazazian, H. H. Jr. MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells. PLoS. Genet. 8, e1002941 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Arjan-Odedra, S., Swanson, C. M., Sherer, N. M., Wolinsky, S. M. & Malim, M. H. Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses. Retrovirology. 9, 53 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Goodier, J. L., Pereira, G. C., Cheung, L. E., Rose, R. J. & Kazazian, H. H. Jr. The broad-spectrum antiviral protein ZAP restricts human retrotransposition. PLoS Genet. 11, e1005252 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Moldovan, J. B. & Moran, J. V. The zinc-finger antiviral protein ZAP inhibits LINE and Alu retrotransposition. PLoS. Genet. 11, e1005121 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang, A. et al. RNase L restricts the mobility of engineered retrotransposons in cultured human cells. Nucleic Acids Res. 42, 3803–3820 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Chiu, Y. L. & Greene, W. C. The APOBEC3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu. Rev. Immunol. 26, 317–353 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Richardson, S. R., Narvaiza, I., Planegger, R. A., Weitzman, M. D. & Moran, J. V. APOBEC3A deaminates transiently exposed single-strand DNA during LINE-1 retrotransposition. Elife 3, e02008 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Beck-Engeser, G. B., Eilat, D. & Wabl, M. An autoimmune disease prevented by anti-retroviral drugs. Retrovirology 8, 91 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Liddicoat, B. J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hartlova, A. et al. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity 42, 332–343 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Shen, Y. J. et al. Genome-derived cytosolic DNA mediates type I interferon-dependent rejection of B cell lymphoma cells. Cell Rep. 11, 460–473 (2015).

    Article  CAS  PubMed  Google Scholar 

  74. West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gehrke, N. et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39, 482–495 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Fowler, B. J. et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346, 1000–1003 (2014). This is the first study challenging the concept that the anti-inflammatory effect of NRTIs is through inhibition of retroviral reverse transcription.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ebert, P. J., Jiang, S., Xie, J., Li, Q. J. & Davis, M. M. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat. Immunol. 10, 1162–1169 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lo, W. L. et al. An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells. Nat. Immunol. 10, 1155–1161 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Young, G. R. et al. Negative selection by an endogenous retrovirus promotes a higher-avidity CD4+ T cell response to retroviral infection. PLoS Pathog. 8, e1002709 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ross, S. R. Mouse mammary tumor virus molecular biology and oncogenesis. Viruses 2, 2000–2012 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tai, A. K. et al. Murine Vβ3+ and Vβ7+ T cell subsets are specific targets for the HERV-K18 Env superantigen. J. Immunol. 177, 3178–3184 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Kershaw, M. H. et al. Immunization against endogenous retroviral tumor-associated antigens. Cancer Res. 61, 7920–7924 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Sacha, J. B. et al. Vaccination with cancer- and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic. J. Immunol. 189, 1467–1479 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Young, G. R., Stoye, J. P. & Kassiotis, G. Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis. Bioessays 35, 794–803 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gonzalez-Hernandez, M. J. et al. Regulation of the human endogenous retrovirus K (HML-2) transcriptome by the HIV-1 Tat protein. J. Virol. 88, 8924–8935 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Szpakowski, S. et al. Loss of epigenetic silencing in tumors preferentially affects primate-specific retroelements. Gene 448, 151–167 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Downey, R. F. et al. Human endogenous retrovirus K and cancer: innocent bystander or tumorigenic accomplice? Int. J. Cancer 137, 1249–1257 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Salmons, B., Lawson, J. S. & Gunzburg, W. H. Recent developments linking retroviruses to human breast cancer: infectious agent, enemy within or both? J. Gen. Virol. 95, 2589–2593 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Cherkasova, E., Weisman, Q. & Childs, R. W. Endogenous retroviruses as targets for antitumor immunity in renal cell cancer and other tumors. Front. Oncol. 3, 243 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Schmitz-Winnenthal, F. H. et al. Potential target antigens for immunotherapy in human pancreatic cancer. Cancer Lett. 252, 290–298 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Malarkannan, S., Serwold, T., Nguyen, V., Sherman, L. A. & Shastri, N. The mouse mammary tumor virus env gene is the source of a CD8+ T-cell-stimulating peptide presented by a major histocompatibility complex class I molecule in a murine thymoma. Proc. Natl Acad. Sci. USA 93, 13991–13996 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Huang, A. Y. et al. The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product. Proc. Natl Acad. Sci. USA 93, 9730–9735 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Schiavetti, F., Thonnard, J., Colau, D., Boon, T. & Coulie, P. G. A human endogenous retroviral sequence encoding an antigen recognized on melanoma by cytolytic T lymphocytes. Cancer Res. 62, 5510–5516 (2002).

    CAS  PubMed  Google Scholar 

  94. Takahashi, Y. et al. Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J. Clin. Invest. 118, 1099–1109 (2008). This is the first report of human cancer regression by recognition of an endogenous retrovirus-derived antigen by cytotoxic T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cohen, C. J., Lock, W. M. & Mager, D. L. Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene 448, 105–114 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Lamprecht, B. et al. Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat. Med. 16, 571–579, 1p (2010).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Renaudineau, Y., Hillion, S., Saraux, A., Mageed, R. A. & Youinou, P. An alternative exon 1 of the CD5 gene regulates CD5 expression in human B lymphocytes. Blood 106, 2781–2789 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Martin, F. J. et al. KMT1E-mediated chromatin modifications at the FcγRIIb promoter regulate thymocyte development. Genes Immun. 16, 162–169 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Sharma, S., Fitzgerald, K. A., Cancro, M. P. & Marshak-Rothstein, A. Nucleic acid-sensing receptors: rheostats of autoimmunity and autoinflammation. J. Immunol. 195, 3507–3512 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. Bhadra, S., Lozano, M. M., Payne, S. M. & Dudley, J. P. Endogenous MMTV proviruses induce susceptibility to both viral and bacterial pathogens. PLoS Pathog. 2, e128 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ribot, J., Romagnoli, P. & van Meerwijk, J. P. Agonist ligands expressed by thymic epithelium enhance positive selection of regulatory T lymphocytes from precursors with a normally diverse TCR repertoire. J. Immunol. 177, 1101–1107 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Punkosdy, G. A. et al. Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. Proc. Natl Acad. Sci. USA 108, 3677–3682 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Myers, L. et al. IL-2-independent and TNF-α-dependent expansion of Vβ5+ natural regulatory T cells during retrovirus infection. J. Immunol. 190, 5485–5495 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Schlecht-Louf, G. et al. Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses. Proc. Natl Acad. Sci. USA 107, 3782–3787 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Antony, J. M. et al. Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat. Neurosci. 7, 1088–1095 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl Med. 7, 307ra153 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Grow, E. J. et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 522, 221–225 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Milner, J. D. & Holland, S. M. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nat. Rev. Immunol. 13, 635–648 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Moir, S., Chun, T. W. & Fauci, A. S. Pathogenic mechanisms of HIV disease. Annu. Rev. Pathol. 6, 223–248 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Morris, G. P. & Allen, P. M. How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat. Immunol. 13, 121–128 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Treangen, T. J. & Salzberg, S. L. Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat. Rev. Genet. 13, 36–46 (2012).

    Article  CAS  Google Scholar 

  115. Hancks, D. C. & Kazazian, H. H. Jr. SVA retrotransposons: Evolution and genetic instability. Semin. Cancer Biol. 20, 234–245 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mager, D. L. & Stoye, J. P. Mammalian Endogenous Retroviruses. Microbiol. Spectr. 3, MDNA3–0009–2014 (2015).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose work could not be cited owing to space restrictions. The authors' work presented in this Review article has been supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council and the Wellcome Trust (102898/B/13/Z to G.K. and 108012/Z/15/Z to J.P.S.).

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Correspondence to George Kassiotis or Jonathan P. Stoye.

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Kassiotis, G., Stoye, J. Immune responses to endogenous retroelements: taking the bad with the good. Nat Rev Immunol 16, 207–219 (2016). https://doi.org/10.1038/nri.2016.27

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