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Let’s start with the scarcely believable, at least until a few years back, and end with the conventional.

ERV-Ws, beneficial viral elements in humans
Remnants of beneficial viruses are embedded in our very DNA. In fact, beneficial viral remnants are central to the continuing existence of not just humans but many other, maybe even all, mammals. The story starts with the decoding of the human genome in the early 2000s. One of the surprises? Endogenous retroviruses (ERVs) comprised ~8% of the human genome. Benefit doesn’t even remotely signify the vital importance of some of these viral remnants.

What’s necessary for any species’ survival? Successful reproduction. As mammals, survival of our developing young requires the unique organ, the placenta. Turns out specific ERVscalled ERV-Ws, in particular the genes, Syncytins1and 2, are essential for mammalian placentation (1, 2, 3). Such a finding provokes the fanciful question, are we reproducing to sustain our species or merely a vehicle supporting the sustenance of ancient viral remnants that subsumed our identity even in the process of seeming to prostrate to our dictates?

How are ERV-Ws essential for our species’ survival?

  • Derived from unique placental cells called villous trophoblasts, syncytiotrophoblasts are the multi-nucleated placental cells that secrete human chorionic gonadotrophin (hCG) and human placental lactogen (hPL), key hormones that facilitate nutrient exchange between mother and fetus.
  • Syncytin-1 and -2 are proteins encoded by the ERV loci, ERVW-1 and ERVFRD-1, located on chromosome 7 and 6, respectively.
  • Syncytins are crucial for syncytiotrophoblast formation (4, 5, 6, 7, 8, 9, 10, 11, 12).
  • How do we know these ERV-derived genes are so important?
    • In vitro human trophoblast cell studies showed that syncytins are necessary for cell fusion necessary to create syncytiotrophoblasts (13).
    • Pre-eclamsia, aka, ‘toxemia of pregnancy‘ is a medical condition where the mother suffers from hypertension and even liver and kidney toxicity. When untreated, it leads to Eclampsia, i.e., seizures, which can be life-threatening for both mother and fetus.
    • Multiple studies have found that syncytin gene expression is reduced in pre-eclampsia, strongly suggesting their role in preventing this serious medical condition (14, 15, 16, 17, 18, 19, 20, 21).
  • Definitive proof of syncytin gene involvement in placentation comes from mouse models.
    • When scientists knocked out mouse Syncytin-1 gene, fetal growth was retarded, placenta structure altered, and pups died in utero (22).
    • When scientists knocked out mouse Syncytin-2 gene, they found impaired syncytiotrophoblasts (23).
  • Thus, expressed in the placenta, independently co-opted multiple times among placental mammals, Syncytin genes are crucial for the formation of syncytiotrophoblasts. See synopsis below on right from 29.
  • Studies now suggest that such viral genes may have been essential in emergence of placental mammals from egg-laying animals (24, 25, 26, 27, 28). See figure below on left from 29.

Examples of conventionally beneficial viruses, CMV (Cytomegalovirus) in humans and MCMV (Mouse CMV) and MNV (Mouse Norovirus) in mice

  • Conventional means not embedded in our very DNA but rather a virus that by itself doesn’t cause fulminant disease but instead appears to induce/sustain immune responses that are more effective in controlling other viruses.
  • Cytomegalovirus (CMV)-seropositive young healthy donors harboring , a common beta-herpesvirus, make stronger antibody responses to influenza vaccination (30, 31). Seropositive means detectable levels of circulating anti-CMV antibodies. This implies these people were likely exposed to/infected with CMV at some point.
  • Interesting details to note here,
    • Most human population is latently infected with CMV. For example, ~60% in >6 years of age and >90% in those >80 years of age in the US (32).
    • Most such infection is benign (33).
    • Most, not all, because CMV is also linked to immunosenescence (immune aging) in the elderly (34). Immunosenscence is associated with higher morbidity and mortality.
    • So is CMV good or bad for humans? How to reconcile such discordant results? Science predicates the synthesis of a coherent explanation that could explain both effects. Mine? ‘The well-adjusted human super-organism is one where their mammalian and microbial components work in harmony to keep pathogens at bay‘ (*).
  • Mice deliberately infected with the mouse version of CMV, namely mouse CMV (MCMV), and then challenged with influenza virus, had reduced influenza virus replication and stronger anti-influenza CD8 T cell response. These data suggest MCMV could be a beneficial virus in mice.
  • Mouse norovirus (MNV) is an example of a beneficial virus in mice (see figure below from 35 summarizing its benefits).


  1. Young, George R., Jonathan P. Stoye, and George Kassiotis. “Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis.” Bioessays 35.9 (2013): 794-803. Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis
  2. Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, et al. 2007. Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA 104: 20534–9. Page on pnas.org
  3. Dupressoir A, Lavialle C, Heidmann T. 2012. From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation. Placenta 33: 663–71.
  4. Blond, J.L.; Beseme, F.; Duret, L.; Bouton, O.; Bedin, F.; Perron, H.; Mandrand, B.; Mallet, F. Molecular characterization and placental expression of herv-w, a new human endogenous retrovirus family. J. Virol. 1999, 73, 1175–1185. Molecular Characterization and Placental Expression of HERV-W, a New Human Endogenous Retrovirus Family
  5. Blond, J.L.; Lavillette, D.; Cheynet, V.; Bouton, O.; Oriol, G.; Chapel-Fernandes, S.; Mandrand, B.; Mallet, F.; Cosset, F.L. An envelope glycoprotein of the human endogenous retrovirus herv-w is expressed in the human placenta and fuses cells expressing the type d mammalian retrovirus receptor. J. Virol. 2000, 74, 3321–3329. An Envelope Glycoprotein of the Human Endogenous Retrovirus HERV-W Is Expressed in the Human Placenta and Fuses Cells Expressing the Type D Mammalian Retrovirus Receptor
  6. Mi, S.; Lee, X.; Li, X.; Veldman, G.M.; Finnerty, H.; Racie, L.; LaVallie, E.; Tang, X.Y.; Edouard, P.; Howes, S.; et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 2000, 403, 785–789.
  7. Frendo, J.L.; Olivier, D.; Cheynet, V.; Blond, J.L.; Bouton, O.; Vidaud, M.; Rabreau, M.; Evain-Brion, D.; Mallet, F. Direct involvement of herv-w env glycoprotein in human trophoblast cell fusion and differentiation. Mol. Cell. Biol. 2003, 23, 3566–3574. Direct Involvement of HERV-W Env Glycoprotein in Human Trophoblast Cell Fusion and Differentiation
  8. Blaise, S.; de Parseval, N.; Benit, L.; Heidmann, T. Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc. Natl. Acad. Sci. USA 2003, 100, 13013–13018. Page on pnas.org
  9. Malassine, A.; Dupressoir A, Marceau G, Vernochet C, Benit L, Kanellopoulos C, Sapin V, Heidmann T. 2005 Syncytin-A and syncytin-B, two fusogenic placenta- specific murine envelope genes of retroviral origin conserved in Muridae. Proc. Natl Acad. Sci. USA 102, 725 – 730. Page on pnas.org
  10. Handschuh, K.; Tsatsaris, V.; Gerbaud, P.; Cheynet, V.; Oriol, G.; Mallet, F.; Evain-Brion, D. Expression of herv-w env glycoprotein (syncytin) in the extravillous trophoblast of first trimester human placenta. Placenta 2005, 26, 556–562. Page on psu.edu
  11. Muir, A.; Lever, A.M.; Moffett, A. Human endogenous retrovirus-w envelope (syncytin) is expressed in both villous and extravillous trophoblast populations. J. Gen. Virol. 2006, 87, 2067–2071. Page on microbiologyresearch.org
  12. Hayward, M.D.; Potgens, A.J.; Drewlo, S.; Kaufmann, P.; Rasko, J.E. Distribution of human endogenous retrovirus type w receptor in normal human villous placenta. Pathology 2007, 39, 406–412).
  13. Vargas, Amandine, et al. “Syncytin-2 plays an important role in the fusion of human trophoblast cells.” Journal of molecular biology 392.2 (2009): 301-318. Syncytin-2 Plays an Important Role in the Fusion of Human Trophoblast Cells
  14. Lee, X., Keith Jr., J.C., Stumm, N., Moutsatsos, I., McCoy, J.M., Crum, C.P., Genest, D., Chin, D., Ehrenfels, C., Pijnenborg, R., van Assche, F.A., Mi, S., 2001. Downregulation of placental syncytin expression and abnormal protein localization in pre- eclampsia. Placenta 22, 808–812. Page on researchgate.net
  15. Keith Jr., J.C., Pijnenborg, R., Van Assche, F.A., 2002. Placental syncytin expression in normal and preeclamptic pregnancies. Am. J. Obstet. Gynecol. 187, 1122–1123 author reply 1123–1124. Page on ajog.org
  16. Knerr, I., Beinder, E., Rascher, W., 2002. Syncytin, a novel human endogenous retroviral gene in human placenta: evidence for its dysregulation in preeclampsia and HELLP syndrome. Am. J. Obstet. Gynecol. 186, 210–213.
  17. Chen, C.P., Wang, K.G., Chen, C.Y., Yu, C., Chuang, H.C., Chen, H., 2006. Altered placental syncytin and its receptor ASCT2 expression in placental development and pre- eclampsia. BJOG 113, 152–158. Altered placental syncytin and its receptor ASCT2 expression in placental development and pre-eclampsia
  18. Chen, C.P., Chen, L.F., Yang, S.R., Chen, C.Y., Ko, C.C., Chang, G.D., Chen, H., 2008. Functional characterization of the human placental fusogenic membrane protein syncytin 2. Biol. Reprod. 79, 815–823. Functional Characterization of the Placental Fusogenic Membrane Protein Syncytin
  19. Kudaka, W., Oda, T., Jinno, Y., Yoshimi, N., Aoki, Y., 2008. Cellular localization of placenta-specific human endogenous retrovirus (HERV) transcripts and their possible implication in pregnancy-induced hypertension. Placenta 29, 282–289.
  20. Langbein, M., Strick, R., Strissel, P.L., Vogt, N., Parsch, H., Beckmann, M.W., Schild, R.L., 2008. Impaired cytotrophoblast cell–cell fusion is associated with reduced Syncytin and increased apoptosis in patients with placental dysfunction. Mol. Reprod. Dev. 75, 175–183.
  21. Vargas, A., Toufaily, C., Lebellego, F., Rassart, E., Lafond, J., Barbeau, B., 2011. Reduced expression of both Syncytin 1 and Syncytin 2 correlates with severity of pre-eclampsia. Reprod. Sci. 18, 1085–1091.
  22. Dupressoir, Anne, et al. “Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene.” Proceedings of the National Academy of Sciences 106.29 (2009): 12127-12132. http://www.pnas.org/content/106/…
  23. Dupressoir A, Vernochet C, Harper F, Guegan J, Dessen P, Pierron G, Heidmann T (2011) A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc Natl Acad Sci USA 108:E1164–E1173.Page on pnas.org
  24. Mi, S.; Lee, X.; Li, X.; Veldman, G.M.; Finnerty, H.; Racie, L.; LaVallie, E.; Tang, X.Y.; Edouard, P.; Howes, S.; et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 2000, 403, 785–789.
  25. Heidmann O, Vernochet C, Dupressoir A, Heidmann T. 2009 Identification of an endogenous retroviral envelope gene with fusogenic activity and placenta- specific expression in the rabbit: a new “syncytin” in a third order of mammals. Retrovirology 6, 107. Page on retrovirology.com
  26. Cornelis G, Heidmann O, Bernard-Stoecklin S, Reynaud K, Veron G, Mulot B, Dupressoir A, Heidmann T. 2012 Ancestral capture of syncytin- Car1, a fusogenic endogenous retroviral envelope gene involved in placentation and conserved in Carnivora. Proc. Natl Acad. Sci. USA 109, E432 – E441. Page on pnas.org
  27. Lavialle, C., Cornelis, G., Dupressoir, A., Esnault, C., Heidmann, O., Vernochet, C., & Heidmann, T. (2013). Paleovirology of ‘syncytins’, retroviral env genes exapted for a role in placentation. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 368(1626), 1471-2970. Page on royalsocietypublishing.org
  28. Lokossou, Adjimon Gatien, Caroline Toudic, and Benoit Barbeau. “Implication of Human Endogenous Retrovirus Envelope Proteins in Placental Functions.” Viruses 6.11 (2014): 4609-4627. Implication of Human Endogenous Retrovirus Envelope Proteins in Placental Functions
  29. Cornelis, Guillaume, et al. “Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials.” Proceedings of the National Academy of Sciences (2015): 201417000. Page on pnas.org
  30. Furman, David, et al. “Cytomegalovirus infection enhances the immune response to influenza.” Science translational medicine 7.281 (2015): 281ra43-281ra43. Cytomegalovirus infection enhances the immune response to influenza
  31. A Virus In Your Mouth Helps Fight The Flu
  32. Staras, Stephanie AS, et al. “Seroprevalence of cytomegalovirus infection in the United States, 1988–1994.” Clinical Infectious Diseases 43.9 (2006): 1143-1151. Seroprevalence of Cytomegalovirus Infection in the United States, 1988-1994
  33. Simanek, Amanda M., et al. “Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States.” PloS one 6.2 (2011): e16103.
  34. Fülöp, T., Anis Larbi, and Graham Pawelec. “Human T cell aging and the impact of persistent viral infections.” Frontiers in immunology 4 (2013). Human T Cell Aging and the Impact of Persistent Viral Infections
  35. Cadwell, Ken. “The Virome in Host Health and Disease.” Immunity 42.5 (2015): 805-813.

* Tirumalai Kamala’s answer to What do we know about the function of viruses in the microbiome?