SARS-CoV-2 spike protein activates human endogenous retroviruses in blood cells

Many diseases in people are now thought to be caused by transposable elements, also called "jumping genes." It's a full-time jump for cells to keep them in check through methylation, RNA binding, or the natural defense system's attention.

We talked about how one type of transposable element, the Line-1 retrotransposons, can be activated in a growing number of neurodegenerative conditions last week. Retrotransposons come from human endogenous retroviruses (HERVs), but most of the time, they don't have the long terminal repeat sequences that make their genes unique at the beginning and end.

On Tuesday, a real bombshell was dropped on the medRxiv preprint website that might explain many of the pathogenic traits of SARS-CoV-2 that have been seen before. The authors provide strong proof that the SARS-CoV-2 spike protein turns on the envelope (ENV) protein encoded by HERV-W in blood cells. This directly causes many of the disease's harmful symptoms. The name HERV-W comes from the fact that many retroviruses in this group use a tryptophan tRNA in their primer binding site. It seems that the name committee thought of the shape of the letter W as akin to the ring structure of atoms in the side chain of tryptophan.

Researchers had already seen a link between the amount of HERV-W ENV protein in T cells and people who had serious breathing problems from SARS-CoV-2. But it wasn't clear what the exact processes were. Now, the real person or thing that set off HERV-W has been found. Researchers added a synthetic trimeric spike protein to SARS-CoV-2 patients' grown peripheral blood mononuclear cells (PBMCs) without making any changes that would make them stable. The RNAs for the ENV protein from both HERV-W and HERV-K were found to be significantly and right away upregulated. It's interesting that only the RNAs for HERV-W led to the development of ENV proteins.

Native spike proteins often refold too quickly into a post-fusion shape, which lowers their ability to activate immune systems and reduces the yields of prefusion trimers. So, mRNA vaccines have small changes that make the mRNA less immunogenic while also making the spike protein it codes for more immunogenic. One way this has been done is by adding two key prolines to the code to make certain conformers more stable. But more study is needed to fully understand how stable spike proteins can cause explosions. Some vaccine makers have taken out the furin cleavage spot from their mRNA construct to make it less likely that a 2-PP stable construct will still fuse. Some of these points were first brought to my attention by an unknown reporter on social media who goes by the name "Underground courtlady."

One important thing that these studies showed was that not all COVID patients had HERV-W ENV activity; about 20% to 30% of them did. This finding probably shows an underlying genetic susceptibility in infected people that needs to be defined and taken into account. This is especially important if HERV-W is to be used as a general indicator of how bad the disease is or as a therapeutic target for a humanized monoclonal antibody therapy, which is what is being planned now. For instance, stimulation of a soluble hexameric form of HERV-W was found in people with multiple sclerosis and is seen as a possible treatment target.

But which HERV-W is it? There are HERV-W fragments in more than 1% of our genomes, which is more than all of our protein-coding regions put together. In fact, the human genome has at least 13 HERV-W sites that contain full-length ENV genes. One of these comes from chromosome 7q21.2 and has an open reading frame for a full HERV-W ENV protein that is not broken up. This protein, Syncytin-1, is well known for playing a key role in proper placental growth. To make things even more complicated, MS now seems to have a lot of different possible roots. A lot of people were excited when researchers announced this week that Epstein-Barr virus illness is a major upstream, downstream, or possibly completely separate cause of MS.

There are other retroviruses besides HERV-W. Scientists have recently found that PEG10, a retrovirus-like protein, binds directly to and releases its own mRNA in virus-like capsids that are outside of cells. This behavior is very much like that of the ARC1 retroviral protein, which is now known to be important for building memories at synapse places. To believe it, scientists are already a long way from changing the type of these virus-like particles by adding fusogens to make an indigenous vector for carrying functional mRNA cargos as a gene therapy. Clearly, some care needs to be taken in these situations (warning: view).

HERV-W ENV was mostly found in endothelial cells from many small blood vessels and in the pleural fatty tissue in heart tissue samples from COVID-19 patients. In this case, CD31 staining proved that the HERV-W ENV-positive cells were vascular. It's scary that HERV-W ENV was found in large amounts in blood clots, nasal passages, and the central nervous system, especially in microglial cells, even though SARS-CoV-2 wasn't found in those areas. The writers say that SARS-CoV-2 caused HERV-W ENV to be expressed in human lymphoid cells, which are cells that don't have the normal ACE2 receptor or the TMPRSS2 enzyme. This means the virus may have other ways to get into these cells. Alternative receptors, such as ASGR1, which is highly expressed in liver cells, may give us a new idea about other possible pathways.

Now more than ever, it's important to know how SARS-CoV-2 turns on HERVs. Transposable elements are known to be activated by and then integrate into sites of active DNA repair. Because of this, it may be worth looking back at earlier studies that claimed to show that reverse transcribed SARS-CoV-2 RNA could integrate into the genome of cultured human cells and then express in tissues from patients. Target site duplications were found on both sides of the viral sequences, as well as consensus LINE1 endonuclease recognition sequences at the integration sites. These findings are in line with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retroposition process.