Role of Endogenous Retroviruses in Human Genetic Diseases


It is now increasingly realised that many repetitive elements such as endogenous retroviruses (ERVs), remnants of ancient retroviral infections, can contribute to the host's genetic and transcriptional identity in complex ways. There is growing evidence that specific ERVs are not genomic ‘junk’, but have biological significance in humans. Some ERVs have been ‘co‐opted’ for human biological processes, and the nucleic acids and proteins of these ERVs are able to modify human gene expression and regulatory networks in a cell and tissue‐specific manner, with implications for healthy development, immune function and susceptibility to diseases. Ongoing research explores the possibility that aberrant expression of HERVs would contribute to the pathogenesis of a number of inflammatory disorders, including cancers, multiple sclerosis, amyotrophic lateral sclerosis and schizophrenia.

Key Concepts

  • Some HERVs have been ‘co‐opted’ for human biological processes such as placentogenesis, innate immunity pathways, anticancer mechanisms and central nervous system function.
  • ERVs provide a genetic reservoir for promoters, transcription start sites, enhancers and alternative splice donors and acceptors for regulating host gene expression.
  • HERV‐K (HML‐2), the youngest HERV in the human genome, is polymorphic in the human population, meaning that not everyone has the same HERV integration at the same chromosomal position.
  • Np9 and Rec, accessory proteins encoded by HERV‐K (HML‐2), are associated with specific human cancers in several ways: their expression is upregulated, they interact with specific cancer biomarkers and they impact signalling pathways that are implicated with cancer.
  • Specific HERV LTRs help regulate the innate immune response by acting as a reservoir of interferon‐inducible enhancers.
  • HERV transcripts play a role in priming and activating B‐cell responses in a T‐cell‐independent pathway against specific pathogens.
  • Ongoing research explores the possibility that aberrant expression of HERVs would contribute to the pathogenesis of a number of inflammatory disorders, including cancers, multiple sclerosis, amyotrophic lateral sclerosis and schizophrenia.

Keywords: endogenous retrovirus (ERV); human endogenous retrovirus (HERV); retroelement; retrotransposon; long terminal repeat (LTR); Env; Np9; Rec; syncytin; autoimmune disease

Figure 1. Genome schematics of endogenous retrovirus and mammalian apparent LTR retrotransposon. (a) Genomic organisation of a HERV‐K (HML‐2) provirus and its 5′ capped and polyadenylated transcripts. The coding sequences of the retroviral genes gag, pro, pol and env are flanked by long terminal repeats (LTRs) at the 5′ and 3′ ends. Each LTR is composed of untranslated 3 (U3), repeat (R) and untranslated 5 (U5) regions. The locations of the primer binding site (PBS), dUTPase and polypurine tract (PPT) are also indicated. Compared to type II HERV‐K (HML‐2) endogenous retroviruses, type I HERV‐K (HML‐2) endogenous retroviruses have a 292 bp deletion in the junction of pol and env, resulting in a different splice donor that produces an np9 transcript instead of rec. (b) Generalised genomic organisation of a mammalian apparent LTR retrotransposon (MaLR). The 5′ and 3′ LTRs are of retroviral origin and flank a putative open reading frame (ORF) region that do not code for any known retroviral proteins.
Figure 2. Model of HERV‐K (HML‐2) in human innate immune function. The transcription factor Oct4 binds to the LTR of a type II HERV‐K (HML‐2) provirus, inducing its transcription. The LTR may also have long‐range enhancer activity on neighbouring host genes. HERV mRNA is processed and translocated to the cytosol for translation. The accessory protein Rec, a product of differential splicing of env transcript, is presumed to translocate into the nucleus and facilitate the export of HERV RNAs into the cytoplasm. The presence of HERV‐K (HML‐2) RNA in the cytosol is detected by the cytosolic immune receptors retinoic acid‐inducible gene‐1 (RIG‐I) and melanoma differentiation‐associated protein 5 (MDA5), which then activates downstream immune signalling processes. The activation of mitochondrial antiviral‐signalling protein (MAVS) results in the activation of NF‐kB, a transcription factor that transalocates to the nucleus where it induces the expression of proinflammatory factors. HERV‐K (HML‐2) mRNA also may be reverse‐transcribed to DNA, which is detected by another cytosolic immune sensor cyclic GMP‐AMP synthase (cGAS), resulting in the production of cGMP that activates stimulator of interferon genes (STING). STING induction leads to the activation of interferon regulatory factors (IRFs) that bind interferon‐stimulated response elements (ISREs) and express type I interferons (IFNs). The release of type I IFNs leads to the activation and clonal expansion of B cells and secretion of antibodies from plasma cells. The HERV‐associated immune response may also result in the expression of interferon‐induced transmembrane proteins (IFITMs) such as IFITM1 that are shown to restrict exogenous viruses. This model depicts findings from Grow et al., and Zeng et al., . * indicates proposed mechanisms.
Figure 3. Model of HERV‐K expression and amyotrophic lateral sclerosis pathogenesis. Motor neurons are susceptible to inflammation due to a combination of genetic predisposition to ALS and environmental factors. Proinflammatory factors TNF‐α and NF‐kB are expressed, inducing the expression of TAR DNA binding protein 43 (TDP‐43) that binds the LTR of HERV‐K, resulting in its expression. env expression has been shown experimentally in transgenic mice to be neurotoxic. The induced expression of HERV‐K may stimulate a neuroinflammatory state, resulting in motor neuron degeneration and symptoms of ALS. This model depicts findings from Li et al. . * indicates proposed mechanisms.
Figure 4. Model HERV‐W Env and multiple sclerosis pathogenesis. Macrophages and activated T cells from blood migrate to the site of neuroinflammation, where they secrete proinflammatory cytokines. Astrocytes, microglia and macrophages have increased expression of HERV‐W Env, which induces secretion of factors that are toxic to oligodendrocytes. Reactive oxygen species (ROS) and cytokines such as interleukin‐1β (IL‐1β) damage oligodendrocytes and may result in the demyelination of the myelin sheaths that wrap around the spinal cord and axons in the brain, resulting in symptoms seen in multiple sclerosis. This model depicts findings from Antony et al., .


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Further Reading

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Lin, Audrey T, and Magiorkinis, Gkikas(Jul 2016) Role of Endogenous Retroviruses in Human Genetic Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026711]