Gervase Vernon is a retired GP from Essex

We are all interested in this new illness, COVID-19, whose nature is gradually being revealed. Will it have a prolonged recovery phase in some people, like glandular fever? If the sudden worsening at day 7 to 10 is due to a cytokine storm, would anti-TNF inhibitors administered early prevent this? Interestingly patients with inflammatory bowel disease on anti-TNF inhibitors, do better than those on other immunosuppressive treatments.(1)

What should we do about the hypercoagulable state?(2) Will COVID-19 lead to lung fibrosis in some patients, like Middle east Respiratory Syndrome, caused by another coronavirus?(3) But, beyond a few virologists, who has noticed that the spike protein of Sars-Cov-2, against which teams are competing to develop a vaccine, is highly homologous with a human HERV protein, syncytin-1.(4) What, indeed, are HERV proteins? What are HERVs?

HERVs are human endogenous retroviruses, that is to say retroviruses whose DNA, over millions of years, has become part of our DNA. All retroviruses, such as HIV, contain viral RNA which is transcribed into DNA and inserted into the host genome. Viral DNA normally leads to the production of more viral RNA, viral proteins and infective particles. In contrast HERV DNA, due to certain faults, is no longer translated into RNA and proteins. Astonishingly 8% of human DNA consists of these preserved but inactive retrovirus DNA sequences, more than is devoted to DNA coding known human proteins. HERVs have been called ’fossil viruses’. They are largely ‘selfish genetic elements’, that is to say that they are reproduced without any benefit to the host, but merely perpetuate themselves as genes.(5)

Will the COVID-19 pandemic trigger the expression of HERV proteins in some patients and lead to the emergence of new diseases as it wanes, just as occurred after the 1918 flu pandemic?

Do any these HERV sequences in our DNA have an active role, or are they all dormant? A few are indeed expressed. Syncytin-1, which is a HERV derived protein, causes fusion of cells in the trophoblast and has a role in placentation. Why should a virus derived protein have a role in cell fusion? Perhaps because fusing to the host cell membrane is a virus’s first task. The expression of other HERV proteins, triggered by viruses, especially EBV, can be harmful.(1) It is now suggested that this is what happens in multiple sclerosis (MS) and type 1 diabetes.(6) In MS raised levels of a particular HERV virus and protein can be found in the CSF and in active MS plaques.(7,8) In the case of MS, the trigger is probably EBV infection.(9) In type 1 diabetes the protein pHERV-W Env is expressed in beta calls.(10) Temelimab, a monoclonal antibody against pHERV-W Env has been trialled in MS and type 1 diabetes. It has had measurable success in MS, initiating remyelination of nerve cells, but no success yet in Type 1 diabetes.(11,12)

That very common disorder, schizophrenia, with a prevalence of 1% of the population, may be associated with the expression of HERVs.(13) It has been known for a long time that schizophrenia can be triggered by infection; there was a large surge in cases after the 1918 influenza pandemic.(14)

Three questions can now be asked about the remarkable homology recorded between SARS-CoV-2 spike protein and HER-W derived protein syncytin-1.(4) Firstly, is that why COVID-19 has adverse effects on pregnancy and child birth? (15) Secondly, is the protection women enjoy relative to men due to immune modulation by the expression of syncytin-1 during childbirth and placentation? If so, do nulliparous women not share that relative protection? It should be straightforward to find this out.

Finally, will the COVID-19 pandemic trigger the expression of HERV proteins in some patients and lead to the emergence of new diseases as it wanes, just as occurred after the 1918 flu pandemic? There are already suggestions that this might be the case for some neurological presentations.(16) Will somebody be measuring syncytin-1 in the CSF of these patients?

 

References

1. Feldmann M, Maini RN, Woody JN, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet. 2020;395(10234):1407‐1409.
2. Liu X, Li Z, Liu S, et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19 [published online ahead of print, 2020 Apr 20]. Acta Pharm Sin B.
3. Memish ZA, Perlman S, Van Kerkhove MD, Zumla A. Middle East respiratory syndrome. Lancet. 2020;395(10229):1063‐1077.
4. Gallaher B. Response to nCoV2019 Against Backdrop of Endogenous Retroviruses [Internet]. Available from: http://virological.org/t/response-to-ncov2019-against-backdrop-of-endogenous-retroviruses/396
5. Orgel LE, Crick FH. Selfish DNA: the ultimate parasite. Nature. 1980;284(5757):604‐607.
6. Levet S, Charvet B, Bertin A, Deschaumes A, Perron H, Hober D. Human Endogenous Retroviruses and Type 1 Diabetes. Curr Diab Rep. 2019;19(12):141.
7. Dolei A. The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis. Mult Scler. 2018;24(1):42‐47
8. Sotgiu S, Mameli G, Serra C, Zarbo IR, Arru G, Dolei A. Multiple sclerosis-associated retrovirus and progressive disability of multiple sclerosis. Mult Scler. 2010;16(10):1248‐1251.
9. Gregson A, Thompson K, Tsirka SE, Selwood DL. Emerging small-molecule treatments for multiple sclerosis: focus on B cells. F1000Res. 2019;8:F1000 Faculty Rev-245. [version 1; referees: 2 approved]. F1000Research. 2019.
10. Levet S, Medina J, Joanou J, et al. An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes. JCI Insight. 2017;2(17):e94387.
11. Temelimab, Multiple Sclerosis Trust [Internet]. [cited 2020 Apr 29]. Available from: https://www.mstrust.org.uk/a-z/temelimab. Acessed 29/04/2020
12. Curtin F, Champion B, Davoren P, et al. A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes. Diabetes Obes Metab. 2020;10.1111/dom.14010.
13. Yolken R. Viruses and schizophrenia: a focus on herpes simplex virus. Herpes. 2004;11 Suppl 2:83A‐88A.
14. Kępińska AP, Iyegbe CO, Vernon AC, Yolken R, Murray RM, Pollak TA. Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Front Psychiatry. 2020;11:72.
15. Di Mascio D, Khalil A, Saccone G, et al. Outcome of Coronavirus spectrum infections (SARS, MERS, COVID 1 -19) during pregnancy: a systematic review and meta-analysis [published online ahead of print, 2020 Mar 25]. Am J Obstet Gynecol MFM. Acessed 30/04/2020 at https://pubmed.ncbi.nlm.nih.gov/32292902/
16. Vetter P, Vu DL, L’Huillier AG, Schibler M, Kaiser L, Jacquerioz F. Clinical features of covid-19. BMJ. 2020;369:m1470

 

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