The Role of HERVs in Covid-19 Patients
HERVs remnants of retroviral germline infections, activated by SARS-CoV-2 in Covid-19 patients.
It Its a confusion when Covid-19 symptoms were not relating with respiratory. From skin rash, diarrhea to neurological symptomps, Covid-19 has indeed put a headache to us. Leave the symptomps, there are some evidences that show SARS-CoV-2, virus that cause Covid-19, is different with the rest of betacoronaviruses. It is indeed a weird virus.
My recent opinion about Superantigens (SAgs) in SARS-CoV-2 had brought me to the few kinds of virus that known to have SAgs. Three of them are HIV, EBV, and HERVs. These three viruses have unique neurological symptoms and I see the red line of them in SARS-CoV-2.
Endogenous retroviruses (ERVs) are endogenous viral elements in the genome that closely resemble and can be derived from retroviruses. There are members of the endogenous retrovirus (group K Gag polyprotein family) that perform different tasks during virus assembly, budding, maturation in SARS-CoV-2.
HERV-W ENV (human endogenous retrovirus -W envelope) was highly expressed in the leukocytes of COVID-19 patients but not the healthy donors. This can be seen from T-cell differentiation and exhaustion and cytokine levels. The percentage of HERV-W ENV-positive lymphocytes correlated with inflammatory markers and pneumonia severity in COVID-19 patients. HERVs, retroviral sequences integrated into the genome during evolution, are now known to represent 8% of the human genome. Inflammatory stimuli may activate HERVs via epigenetic dysregulation.
An initial exposure to SARS-CoV-2 virus activates early HERV-W and K transcription in Peripheral Blood Mononuclear Cell (PBMC) cultures from healthy donors. A peripheral blood mononuclear cell (PBMC) is any blood cell having a round nucleus such as lymphocyte, monocyte or macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. After a week, only HERV-W ENV protein expression was detected in lymphoid cells of some donors, although SARS-CoV-2 infection of PBMC was not observed. Exposure to SARS-CoV-2 also triggers HERV-W envelope production in T-cells of heathy individuals. Human cell-line expressing ACE2/TMPRSS2 produces HERV-W ENV protein following SARS-CoV-2 infection. Exposure to SARS-CoV-2 protein induced a significant production of interleukin 6 in another healthy PBMC, an evidence that the observed HERV activation is not induced by cytokines, or by inflammation due to viral infection, but rather by SARS-CoV-2 spike protein itself.
Viral infection examples: EBV and HIV. The EBV (Eipstein Barr Virus) gp350 protein has been shown to activate HERV-W in vitro in B cells and monocytes, but not in T cells, whereas monocyte/macrophage cells appear to be most susceptible. EBV and HIV-1 (HIV Tat protein, enhances the efficiency of viral transcription) can act as a trigger. Env protein of HERV-W particles induced proinflammatory and superantigen (SAg)-like effects.
• HERV-W envelope protein was shown high in Covid-19 patients' lymphocytes.
• HERV could compromise the immune system and facilitate to the infection.
• SARS-CoV-2 spike protein induces HERVs.
• HERV can make Covid-19 undetectable.
• HERV can make proviral genes and help incapable-transmit-to-human animal isolate to be infectious to human.
• HERV may help SARS-CoV-2 to modulate the translation start for the ribosome to change the pattern of COVID-19 orfs in different human hosts.
Exposure to either exogenous viruses or traumatic experiences can activate HERVs in the brain to cause depressive (and possibly other psychiatric) symptoms. HERVs can cause Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with symptomps joint pains, mood disturbance, and malaise and worsening of symptoms following minimal physical or mental exertion. More severe symptoms can be also present including extreme exhaustion, severe joint pains with no apparent cause, non-restorative sleep and a range of immune and neurological symptoms. These symptoms may lead to depression and social isolation in the patient.
Possible Role for HERVs in COVID-1
HERVs or their products could compromise the immune system and facilitate the infection and penetrance of the SARS-CoV-2 to human cells. Also, individuals with high levels of the ACE2 receptor could be an easy target for the virus, especially those with high blood pressure and various types of stress.
Different SARS-CoV-2 isolates from the same country or from different countries have various orf (open reading frame) patterns, thus various outcomes. Some of the produced orfs is the enzyme responsible for methylation of the 2’ carbon of the ribose sugar of viral RNA. HERVs could produce protein products that complement the SARS-CoV-2 set of orfs in its entry, infection, replication, packaging, and integration in the human genome. In addition, partial proviral genomes of previous integration can produce some enzymes required for the replication of viral isolates that do not have the infection ability. For example, one animal isolate which does not have the capability to infect human could transfer to human and find in this individual’s genome some proviral genes that complement the animal strain to be infectious and able to cause the symptoms.
Corona virus Genome can only produce its effective proteins for viral reproduction with 1ribosomal slippage at the translation start site. HERVs may produce proteins or miRNA that modulates the translation start for the ribosome changing the pattern of COVID-19 orfs in different human hosts. This leads to different course of symptoms and severity of the COVID-19 infection.
If HERV-W ENV is identified quite early in COVID-19 patients, it may significantly contribute to a delayed onset of immunopathological and/or neurological syndromes.
Sources:
https://link.springer.com/article/10.3103/S0095452720060031
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00134-1/fulltext
https://www.sciencedirect.com/science/article/pii/S1201971220325753
https://www.sciencedirect.com/science/article/pii/S1471491418300315
https://www.sciencedirect.com/science/article/pii/S1471491418300315#bib0155
https://www.biorxiv.org/content/biorxiv/early/2020/03/31/2020.03.28.013789.full.pdf
https://www.sciencedirect.com/science/article/abs/pii/S0306987719308849
https://autoimmunhighlights.biomedcentral.com/articles/10.1186/s13317-019-0122-8
https://en.m.wikipedia.org/wiki/Endogenous_retrovirus#:~:text=Endogenous%20retroviruses%20(ERVs)%20are%20endogenous,lower%20estimates%20of%20~1%25).
https://www.researchsquare.com/article/rs-301236/latest.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673925/
How long can this changes persist? Will these neurologic sympthoms become a real chronic disease?