Review Article | Published:

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

Nature Reviews Immunology volume 16, pages 207219 (2016) | Download Citation

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.

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.

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References

  1. 1.

    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).

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

    & Murine endogenous retroviruses. Cell. Mol. Life Sci. 65, 3383–3398 (2008).

  8. 8.

    & The impact of retrotransposons on human genome evolution. Nat. Rev. Genet. 10, 691–703 (2009).

  9. 9.

    & Effects of retroviruses on host genome function. Annu. Rev. Genet. 42, 709–732 (2008).

  10. 10.

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

  11. 11.

    , & Identification, phylogeny, and evolution of retroviral elements based on their envelope genes. J. Virol. 75, 11709–11719 (2001).

  12. 12.

    , , & Identification of endogenous retroviral reading frames in the human genome. Retrovirology 1, 32 (2004).

  13. 13.

    , , , & 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).

  14. 14.

    , , & Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8, 90 (2011).

  15. 15.

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

  16. 16.

    & Reconstitution of an infectious human endogenous retrovirus. PLoS Pathog. 3, e10 (2007).

  17. 17.

    , & Keeping active endogenous retroviral-like elements in check: the epigenetic perspective. Cell. Mol. Life Sci. 65, 3329–3347 (2008).

  18. 18.

    & Dynamic control of endogenous retroviruses during development. Virology 411, 273–287 (2011).

  19. 19.

    , & Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity. Rev. Med. Virol. 19, 273–286 (2009).

  20. 20.

    , , , & Role of endogenous retroviruses in murine SLE. Autoimmun. Rev. 10, 27–34 (2010).

  21. 21.

    & Active human retrotransposons: variation and disease. Curr. Opin. Genet. Dev. 22, 191–203 (2012).

  22. 22.

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

  23. 23.

    , , & Endogenous retroviral pathogenesis in lupus. Curr. Opin. Rheumatol. 22, 483–492 (2010).

  24. 24.

    , , , & Endogenous retroviruses and cancer. Cell. Mol. Life Sci. 65, 3366–3382 (2008).

  25. 25.

    & 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.

  26. 26.

    & The diversity of retrotransposons and the properties of their reverse transcriptases. Virus Res. 134, 221–234 (2008).

  27. 27.

    & Origin and evolution of retroelements based upon their reverse transcriptase sequences. EMBO J. 9, 3353–3362 (1990).

  28. 28.

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

  29. 29.

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

  30. 30.

    & Human transposon tectonics. Cell 149, 740–752 (2012).

  31. 31.

    & Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135, 23–35 (2008).

  32. 32.

    , & L1 retrotransposons and somatic mosaicism in the brain. Annu. Rev. Genet. 48, 1–27 (2014).

  33. 33.

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

  34. 34.

    , , & Retrotransposition and crystal structure of an Alu RNP in the ribosome-stalling conformation. Mol. Cell 60, 715–727 (2015).

  35. 35.

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

  36. 36.

    & Long terminal repeat retrotransposons of Mus musculus. Genome Biol. 5, R14 (2004).

  37. 37.

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

  38. 38.

    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.

  39. 39.

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

  40. 40.

    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).

  41. 41.

    , , , & Env-less endogenous retroviruses are genomic superspreaders. Proc. Natl Acad. Sci. USA 109, 7385–7390 (2012).

  42. 42.

    , & 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.

  43. 43.

    & 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.

  44. 44.

    , , & 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).

  45. 45.

    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).

  46. 46.

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

  47. 47.

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

  48. 48.

    & 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).

  49. 49.

    , , , & The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes. Proc. Natl Acad. Sci. USA 112, 8367–8372 (2015).

  50. 50.

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

  51. 51.

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

  52. 52.

    , , & Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).

  53. 53.

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

  54. 54.

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

  55. 55.

    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).

  56. 56.

    , & Emerging roles of TLR7 and TLR9 in murine SLE. J. Autoimmun. 33, 231–238 (2009).

  57. 57.

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

  58. 58.

    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.

  59. 59.

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

  60. 60.

    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).

  61. 61.

    , , & Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).

  62. 62.

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

  63. 63.

    , & MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells. PLoS. Genet. 8, e1002941 (2012).

  64. 64.

    , , , & Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses. Retrovirology. 9, 53 (2012).

  65. 65.

    , , , & The broad-spectrum antiviral protein ZAP restricts human retrotransposition. PLoS Genet. 11, e1005252 (2015).

  66. 66.

    & The zinc-finger antiviral protein ZAP inhibits LINE and Alu retrotransposition. PLoS. Genet. 11, e1005121 (2015).

  67. 67.

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

  68. 68.

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

  69. 69.

    , , , & APOBEC3A deaminates transiently exposed single-strand DNA during LINE-1 retrotransposition. Elife 3, e02008 (2014).

  70. 70.

    , & An autoimmune disease prevented by anti-retroviral drugs. Retrovirology 8, 91 (2011).

  71. 71.

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

  72. 72.

    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).

  73. 73.

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

  74. 74.

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

  75. 75.

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

  76. 76.

    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.

  77. 77.

    , , , & 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).

  78. 78.

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

  79. 79.

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

  80. 80.

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

  81. 81.

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

  82. 82.

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

  83. 83.

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

  84. 84.

    , & Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis. Bioessays 35, 794–803 (2013).

  85. 85.

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

  86. 86.

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

  87. 87.

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

  88. 88.

    , & Recent developments linking retroviruses to human breast cancer: infectious agent, enemy within or both? J. Gen. Virol. 95, 2589–2593 (2014).

  89. 89.

    , & Endogenous retroviruses as targets for antitumor immunity in renal cell cancer and other tumors. Front. Oncol. 3, 243 (2013).

  90. 90.

    et al. Potential target antigens for immunotherapy in human pancreatic cancer. Cancer Lett. 252, 290–298 (2007).

  91. 91.

    , , , & 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).

  92. 92.

    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).

  93. 93.

    , , , & A human endogenous retroviral sequence encoding an antigen recognized on melanoma by cytolytic T lymphocytes. Cancer Res. 62, 5510–5516 (2002).

  94. 94.

    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.

  95. 95.

    , & Endogenous retroviral LTRs as promoters for human genes: a critical assessment. Gene 448, 105–114 (2009).

  96. 96.

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

  97. 97.

    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).

  98. 98.

    , , , & An alternative exon 1 of the CD5 gene regulates CD5 expression in human B lymphocytes. Blood 106, 2781–2789 (2005).

  99. 99.

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

  100. 100.

    , , & Nucleic acid-sensing receptors: rheostats of autoimmunity and autoinflammation. J. Immunol. 195, 3507–3512 (2015).

  101. 101.

    , , & Endogenous MMTV proviruses induce susceptibility to both viral and bacterial pathogens. PLoS Pathog. 2, e128 (2006).

  102. 102.

    , & 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).

  103. 103.

    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).

  104. 104.

    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).

  105. 105.

    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).

  106. 106.

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

  107. 107.

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

  108. 108.

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

  109. 109.

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

  110. 110.

    , & Pathogenic mechanisms of HIV disease. Annu. Rev. Pathol. 6, 223–248 (2011).

  111. 111.

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

  112. 112.

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

  113. 113.

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

  114. 114.

    & Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat. Rev. Genet. 13, 36–46 (2012).

  115. 115.

    & SVA retrotransposons: Evolution and genetic instability. Semin. Cancer Biol. 20, 234–245 (2010).

  116. 116.

    & Mammalian Endogenous Retroviruses. Microbiol. Spectr. 3, MDNA3–0009–2014 (2015).

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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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Affiliations

  1. Retroviral Immunology, the Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, UK.

    • George Kassiotis
  2. Department of Medicine, Faculty of Medicine, Imperial College London, London W2 1PG, UK.

    • George Kassiotis
    •  & Jonathan P. Stoye
  3. Retrovirus-Host Interactions, the Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, UK.

    • Jonathan P. Stoye

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The authors declare no competing financial interests.

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Correspondence to George Kassiotis or Jonathan P. Stoye.

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https://doi.org/10.1038/nri.2016.27

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