Does SARS-CoV-2 reverse transcribe and integrate into our genome? — Deplatform Disease

  1. Some patients have persistently positive PCRs, suggesting that viral genome sequences are being retained.
  2. The presence of chimeric sequences (sequences with both human and viral components) on RNA-seq (more on what this means shortly, I promise).
  1. SARS-CoV-2 is not a retrovirus. It has no means of producing a DNA transcript nor integrating it into a host’s genome. The argument made in this preprint is not that SARS-CoV-2 itself is doing the reverse transcription and integration, however.
  2. Endogenous human reverse transcription is extremely rare and limited to a few genetic entities, and occurs in a sequence-specific manner. It is extremely implausible that host reverse transcriptases could pick up random cytosolic RNA and simply place it into the genome, discussed in more detail here.
  3. Coronaviruses kill the cells they infect; it would be very unusual to see a virus that is lethal to the cells it infects integrate, and furthermore, as long as they had a coronavirus infection the cells would eventually die.
  1. Immunological suppression via multiple mechanisms:
    Direct or indirect killing of the cells of the immune system e.g. HIV can induce the expression of the Fas ligand protein on infected cells, which can induce killing of activated T cells that come into contact with it through signaling using the Fas on the surface of the T cell.
    Suppressing function of antibodies e.g. herpes simplex virus type 1 (HSV-1) contains proteins that bind antibodies and prevent them from activating the complement system.
    Suppression of production of antiviral cytokines e.g. Epstein-Barr virus (EBV) interferes with TLR signaling to suppress the activation of the NFκB pathway that would go on to induce multiple antiviral cytokines.
  2. Maintenance of a viral reservoir within an immunologically privileged site e.g. the central nervous system, the testicles, etc. as seems to be done by Ebola.
  3. Latency wherein the viral genome exists as a separate DNA structure within the nucleus where it remains quiescent with reactivation under certain cues. This is done by herpesviruses.
  1. The sequence would behave like a processed pseudogene, lacking any ability to recruit host transcription machinery and would sit in the genome, quiescent.
  2. If the sequence somehow inserted downstream of a promoter sequence that could recruit transcription machinery, the cell would express spike protein, be recognized by the immune system, and then be killed.
  3. If the sequence inserted itself into the middle of gene (specifically in the middle of an exon), you would get a mutant protein that had sequences from SARS-CoV-2 that would be processed by antigen-presenting machinery and trigger a T cell response that killed the cell.

References

  1. Alexandersen S, Chamings A, Bhatta TR. 2020. SARS-CoV-2 genomic and subgenomic RNAs in diagnostic samples are not an indicator of active replication. Nat Commun. 11(1):6059.
  2. Boldogh I, Albrecht T, Porter DD. 2011. Persistent Viral Infections. In: Baron S, editor. Medical Microbiology. Galveston (TX): University of Texas Medical Branch at Galveston.
  3. Cohen JI. 2020. Herpesvirus latency. J Clin Invest. 130(7):3361–3369.
  4. Feschotte C, Gilbert C. 2012. Endogenous viruses: insights into viral evolution and impact on host biology. Nat Rev Genet. 13(4):283–296.
  5. Flint SJ, Enquist LW, Racaniello VR, Rall GF, Skalka AM. 2015. Principles of Virology: 2 Vol set — Bundle. 4th ed. Washington, D.C., DC: American Society for Microbiology.
  6. Hilleman MR. 2004. Strategies and mechanisms for host and pathogen survival in acute and persistent viral infections. Proc Natl Acad Sci U S A. 101 Suppl 2(Supplement 2):14560–14566.
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  8. Lodish H, Berk A, Kaiser C, Krieger M, Bretscher A, Ploegh H, Amon A, Martin K. Molecular cell biology. 8th ed. New York: W.H. Freeman; 2016
  9. Lubinski JM, Jiang M, Hook L, Chang Y, Sarver C, Mastellos D, Lambris JD, Cohen GH, Eisenberg RJ, Friedman HM. 2002. Herpes simplex virus type 1 evades the effects of antibody and complement in vivo. J Virol. 76(18):9232–9241.
  10. Perlman S, Dandekar AA. 2005. Immunopathogenesis of coronavirus infections: implications for SARS. Nat Rev Immunol. 5(12):917–927.
  11. The Sagan standard: Extraordinary claims require extraordinary evidence. Effectiviology.com. [accessed 2020 Dec 16]. https://effectiviology.com/sagan-standard-extraordinary-claims-require-extraordinary-evidence/.
  12. V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. 2020. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. doi:10.1038/s41579–020–00468–6. http://dx.doi.org/10.1038/s41579-020-00468-6.
  13. Wiedemann A, Foucat E, Hocini H, Lefebvre C, Hejblum BP, Durand M, Krüger M, Keita AK, Ayouba A, Mély S, et al. 2020. Long-lasting severe immune dysfunction in Ebola virus disease survivors. Nat Commun. 11(1):3730.
  14. Younesi V, Nikzamir H, Yousefi M, Khoshnoodi J, Arjmand M, Rabbani H, Shokri F. 2010. Epstein Barr virus inhibits the stimulatory effect of TLR7/8 and TLR9 agonists but not CD40 ligand in human B lymphocytes: Inhibition of TLR stimulation by EBV. Microbiol Immunol. 54(9):534–541.

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Edward Nirenberg

Edward Nirenberg

I write about vaccines here. You can find me on Twitter @enirenberg and at deplatformdisease.com (where I publish the same content without a paywall)