This article will be a little bit different, and somewhat “layperson” friendly, and I will build a more complex analysis after since this is one of the most important aspects of this whole puzzle. Also unlike my usual self, this time I would appreciate it if you shared this anywhere you wish.
To be abundantly clear, similar to the PAID hypothesis, this was a byproduct of doing research with the same friend, this was that person's “brainchild”, its specialty. One day I would end up here, but not as “early”. Credit where it is due. If you are reading this, I miss you, friend.
Among the many roads traveled in search for answers and missing pieces of the puzzle, we reached the conclusion that SARS-CoV-2 and its unique Spike Protein was potentially “flipping a switch”, a switch so important, so primordial, that this effect was partially responsible for most of the entire physiological cascade. Later we both agreed it there was an entirely different degree of complexity to it, but this switch played a significant and disproportional role. Later the friend demonstrated the switch flipped was HERVs. This later moment was in September 2021.
In case you are asking yourself why I took so long to write about this, it is because there were many missing pieces, and I prefer doing thorough research and understanding things to the best of my ability. I also promised I would never write about it, but given the intersection of HERVs and most of what I wrote, I decided to write, that its importance shouldn’t be overlooked any further.
First, we need an explanation. What are HERVs ?
HERVs, or Human Endogenous Retroviruses, are remnants of ancient retroviral infections that integrated their genetic material into the human genome over millions of years. They make up 8% of our genomes. HERVs integrate themselves into our DNA through a process called retrotransposition. This process involves the conversion of the retroviral RNA genome into DNA by the enzyme reverse transcriptase, which is carried by the virus. Once the viral RNA is reverse-transcribed into DNA, the resulting DNA molecule, known as a provirus, can integrate into the host cell's genome. During integration, the provirus inserts itself into a random location in the host cell's DNA.
This integration is mediated by an enzyme called integrase, which helps the provirus become a permanent part of the host genome. Once integrated, the provirus can be passed on to subsequent generations as the host cell divides. Over time, many HERVs have accumulated in the human genome through repeated retrotransposition events. However, most of these HERVs have accumulated mutations that have rendered them inactive and unable to produce infectious virus particles. Despite their inactivity, these HERVs can still influence gene regulation and cellular processes in various ways.
HERVs regulation (repression or expression) is complex and regulated by many important steps, but in simplistic terms, you just need proper methylation and a good (functional) immune system. HERVs play a role in both health and disease, but my focus here will be primarily on the disease part.
Do HERVs play a role in SARS-CoV-2 infection and immunological responses ?
Expression of inflammatory markers is closely correlated with the expression of HERVs. It can be used as a biomarker and predictor of disease severity, similar to other biomarkers, shown below. “HERW-W with N-SARS, IL-10, IL-6, and TNF-α and another component outlined HERV-K with TLR-3, TLR-7, MCP-1, and the IL-17RA in individuals who underwent hospitalization”, meaning each set of a specific HERV with specific inflammatory markers denotes a different group of hospitalized patients.
HERVs expression is closely related to different mechanisms with the most pertinent to our conversation being uncontrolled inflammatory responses, as per the graphic above, the ENV (Envelope) protein increases with Covid severity, and the higher the severity, in more cells it can be found. In another study, the researchers found “HERV-W ENV antigenemia is also seen to persist over one-year post-infection suggesting that chronic expression is made possible after COVID-19 as seen to be lifelong in multiple sclerosis”. In a study of patients with psychosis spectrum disorders, yet again an overwhelming influence of the virus with HERV-W ENV expression and long-term inflammation.
So in some post-Covid (Long Covid) there is a persistent, sustained expression of HERV-W ENV, meaning the cells continuously keep producing. Once again there is an intersection between immune dysfunctional states, persistent long-term inflammation, and the expression of pathogenic HERVs, creating our theoretical “doom loop”.
The many metabolic and cellular pathways in regards to Covid are the perfect example of “double-edge swords”, HERVs are the primordial example of “too much of anything is bad for you”. Summarizing so far, HERVs expression follows the higher levels of strongly inflammatory proteins, which in turn influence the expression of HERVs, and HERVs levels are related to severity and to Long Covid. Our next step is doing my preferred analytical method, connecting the dots.
The many pathways and role of HERVs in Paradoxically Acquired Immune Dysfunction
At every turn and from every perspective you look, you will find that the virus, but especially the vaccines often induce a lasting Th17 immune response, a highly inflammatory state. To the surprise of no one at this point, HERV-K dUTPase (an essential enzyme for DNA metabolism, I mentioned it recently and told you it would be important) can influence and induce a Th17 response, by making cells produce “IL-12p40, IL-23, IL-17, tumor necrosis factor-α, IL-8, and CCL20, in dendritic/Langerhans-like cells and to a lesser extent in keratinocytes”. Given the significance and negative impact of sustained higher levels of IL12, IL17, and the T Helper cells 17 (Th17) in many different autoimmune diseases, in both severe disease and the many long-term adverse effects in Long Covid, this alone proves to be of interest. Th17 in the presence of IL-6 has also been implicated in viral persistence, about to be really important. Notably and significantly, Herpesviruses can usurp IL-17 to both establish latency and possibly reactivate themselves.
A list of HERVs and their involvement in various diseases.
HERVs involve in the pathology of various diseases, including cancers (Burns, 2017; Fischer et al., 2016; Gao et al., 2021; Kassiotis, 2014; Mullins and Linnebacher, 2012; Yu et al., 2013), autoimmune diseases (Anand et al., 2017; Balada et al., 2009; Brodziak et al., 2012; Nelson, 1995; Tugnet et al., 2013) and neurological diseases (Antony et al., 2011; Giménez-Orenga and Oltra, 2021; Gröger et al., 2021). The important topics have been extensively reviewed elsewhere (Garcia-Montojo et al., 2018; Hohn et al., 2013). Many studies report that transcripts and products of HERVs are detected in various cancers; breast cancers, ovarian cancers (Wang-Johanning et al., 2007), lymphoma (Contreras-Galindo et al., 2008), melanoma (Serafino et al., 2009), germline tumors (Herbst et al., 1996), leukemia (Depil et al., 2002), prostate cancer (Goering et al., 2011), and colon cancer (Dolci et al., 2020). HERVs are also involved in the development of autoimmune diseases such as multiple sclerosis (MS) (Garson et al., 1998; Komurian-Pradel et al., 1999; Rasmussen et al., 1995), rheumatoid arthritis (RA) (Freimanis et al., 2010; Mameli et al., 2017; Nakagawa et al., 1997), systemic lupus erythematosus (SLE) (Blomberg et al., 1994), as well as neurological diseases such as ALS (Li et al., 2015; Mayer et al., 2018), ASD (Balestrieri et al., 2012; 2019), attention deficit hyperactivity disorder (ADHD) (Anand et al., 2017; Cipriani et al., 2018; D'Agati et al., 2016), FM (Ovejero et al., 2020; Rodriguez-Pintó et al., 2014), schizophrenia (Huang et al., 2011; Karlsson et al., 2004; Perron et al., 2008; 2012), and bipolar disorder (BD) (Fries et al., 2019; Giménez-Orenga and Oltra, 2021; Goldsmith et al., 2016; Perron et al., 2012). This is likely to a continuing and growing list of diseases in which HERVs are involved in the pathology.
HERVs will often work “together” with other pathogens contributing to different diseases, the role of HERVs in cancer is extensive such as K and H in prostate cancer, but they also play a role in Type 1 Diabetes (HERV-W here), K10 in rheumatoid arthritis, K can induce neurodegeneration by interacting with the important Toll Like Receptor 7, 8 and the list of complex relationships goes on and on. HERVs are often activated (meaning your body will start “producing” it) by NF-Kb one of the most important steps in cellular response. But there is another way, more pernicious and pertinent to this situation and its long-term effects.
HERVs can be expressed by, and have a very interesting relationship with Herpesviruses. The following articles should be considered “must read”, the second, primarily for covering superantigens.
CMV induces HERV-K and HERV-W expression, HERVs have a pretty categorized role in the development of Multiple Sclerosis, and so do Herpesviruses, HHV-6 can induce the expression of a Multiple Sclerosis Associated Retrovirus (MSRV), and the envelope of MSRV can trigger TLR4 inducing inflammatory responses. I think it is interesting to bring up the role of EBV and HERV expression and the potential for Vitamin D levels to affect both. The following citation from another paper “Direct HERV-mediated toxicity or aberrant immune activation by HERV components can then induce MS. This model suggests multiple therapeutic targets (EBV, HERV, vitamin D metabolism), and elucidation of the exact interplay between these factors might lead to new treatment strategies for MS.”
To my own surprise, EBV can induce the expression of a HERV-K18 superantigen, and so HHV-6A can induce the same superantigen. The presence of this superantigen is elevated in juvenile rheumatoid arthritis. As I wrote in my substack referred to above, superantigens would play a significant role.
One of the hallmarks of SARS-CoV-2 long-term (months) damage, and Long Covid are both progressive insulin resistance developing poor control of the sugar levels in the body, which incidentally induces dozens of metabolic reactions and low-grade inflammation, the second being the immunological dysfunction many develop, with all its subgroups.
While the focus of the paper cited above focuses on other superantigens, given the puzzling chimeric nature of the endotoxin LPS, being able to bind to other proteins and other toxins to induce similar severely inflammatory responses, we now can deduce a possible mechanism for a lot of the continuous injury, from clotting to autoimmune diseases at different timeframes, since each human body is unique.
SARS-COV-2 Spike Protein (virus at higher levels, vaccine at each dose) > has a superantigen-like pocket > can interact and usurp LPS to heighten or create a super inflammatory response > induces expression of HERVs and at the same time > reactivates latent viruses > HERVs interact with latent viruses and create new superantigenic reactions > repeat step two, endotoxemia = endotoxin floating in your blood, freely
“How is everyone not dead ?” may have crossed your mind, and I am glad if it did. Chronic exposure to superantigen, as proposed (there are other mechanisms), can induce your CD4+ regulatory cells with IL-10 (an anti-inflammatory, immunosuppressive protein) can suppress the immune response created by superantigen. IL-10 has been proposed to participate and is necessary to develop IgG4 responses.
We now have many pieces of this part of the puzzle (always remember, my work is just a minor fraction of the complexity of SARS-CoV-2), and two sides of the coin. On one side, the hyper-inflammatory, aggressive responses, and its many cascade effects, and on the other how potentially the body compensated for the exposure to the Spike Protein and other superantigens. All aspects covered recently entail long-term problems, and the best way to deal with all of this is a healthy lifestyle. A smaller Part II will come on Thursday.
Here is a little tidbit of interesting information. I have hinted on HERVs for a long time now. https://hiddencomplexity.substack.com/p/china-approves-hiv-drug-for-covid
Azivudine, China almost miracle drug against SARS-CoV-2 has anti-HIV effects (HIV is a retrovirus) and has also anti-cancer effects, and most likely this comes from being able to disrupt HERVs.
The "Things Hidden" in the title isn't merely for effect or literary reference hehe.
You've been writing about Gal-3 for some time, and it's great to convey that these pathologies aren't occurring in isolation.
It also makes medical diagnosis & treatment a significant, multistep challenge (if they ever get there at all?)
LPS-Induced Galectin-3 Oligomerization Results in Enhancement of Neutrophil Activation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198732/