Resurrection of endogenous retroviruses during aging reinforces senescence, 2023, Liu et al

[SNT Gatchaman]

Resurrection of endogenous retroviruses during aging reinforces senescence
Liu X, Liu Z, Wu Z, Ren J, Fan Y, Sun L, Cao G, Niu Y, Zhang B, Ji Q, Jiang X, Wang C, Wang Q, Ji Z, Li L, Esteban CR, Yan K, Li W, Cai Y, Wang S, Zheng A, Zhang YE, Tan S, Cai Y, Song M, Lu F, Tang F, Ji W, Zhou Q, Belmonte JCI, Zhang W, Qu J, Liu GH. R

Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown.

In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging.

These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.

Link | PDF (Cell)

 

[Hutan]

Thanks for posting this @SNT Gatchaman. In the context of what we were talking about the other day, about how similar ME/CFS symptoms are to those of our very eldest relatives, I think the idea of human endogenous retrovirus reactivation makes for an intriguing hypothesis.

I need to read it again carefully, with a list of deciphered acronyms readily to hand.

I think it makes sense that these endogenous retroviruses might awaken when a pathogen acts to reduce the body's capacity to control viruses. We've seen evidence that various pathogens do actively disable the body's immunity defences, and many of us have experienced latent viruses such as HSV-1 reactivating during PEM.

It seems that the human endogenous retroviruses produce retrovirus-like particles that are able to make healthy cells become senescent.

Extracellular HERVK RVLPs induce cellular senescence

Previous studies indicated that tumor cell-derived HERVK RVLPs could be released into the culture medium and then taken up by other cells.54 Given that the presence of HERVK RVLPs in senescent cells was observed in this study (Figures 2C, 2D, and S2D–S2F), we asked whether HERVK RVLPs produced by senescent cells could be released extracellularly and convey senescence signals to non-senescent cells (Figure 5A).

After SC-CM treatment, we observed an increased HERVK abundance in young hMPCs (Figure 5F), implying that HERVK in SC-CM may be trans- mitted into target cells.

(SC_CM is senescent-cell conditioned medium; hMPC are a type of human cell)

Could these particles be the 'something in the blood'?

There have been and are some studies on HERV's in ME/CFS (click on the HERV tag above to see some of them).

 

[SNT Gatchaman]

See also the thread on Temelimab, a monoclonal antibody against a HERV-W glycoprotein, which the Swiss are trialling in long COVID (also being evaluated for MS).

 

[SNT Gatchaman]

A little more on HERVs in MS, which I'll put here in this non-ME thread. Please see also threads tagged with herv.

These are a few background papers relating to the cascade as a hypothetical mechanism in MS. (I think it might be summarised as: "some-virus" or immune challenge -> immune dysregulation -> loss of immune control of latent virus -> EBV/HHV (trans)activation <-> HERV expression -> "badness").

These papers all relate to multiple sclerosis. The first (2021) paper is a comprehensive overview, containing the following —

Dysregulated (virus- or cytokine-induced) expression of HERV-K/-W elements have clear implications for the pathogenesis of multiple neurological disease, including MS, secondary to the initial triggering by EBV-driven mechanisms.

Together, these observations strengthen the 3-viral cascade hypothesis, with EBV as leading pathogen and comprising a multi-factorial interaction of virus-, altered self or mimicry- and cytokine-driven inflammatory pathogenic events underlying the different manifestation of MS disease, being nonprogressive (CIS), reiterating (RRMS) and progressive (SPMS, PPMS) with increasing neurological damage.

The possible roles of different HERV family members in MS have been comprehensively reviewed recently, including how immune activation, inflammation, and oxidative stress can influence the transcription of HERV genes.

There's also the interesting suggestion that MS ± various autoimmune conditions could have their female predisposition explained by a pathological HERV incompletely encoded on the X chromosome.

However, it has been proposed that pHERV-W env may be derived from a HERV-W gene on the X chromosome at Xq22.3, which has a premature stop codon at position 39, through a process of somatic mutation or trans-splicing.

• Cumulative Roles for Epstein-Barr Virus, Human Endogenous Retroviruses, and Human Herpes Virus-6 in Driving an Inflammatory Cascade Underlying MS Pathogenesis (2021, Frontiers in Immunology)
• Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How? (2018, Molecular Neurobiology)
• The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis (2018, Multiple Sclerosis Journal)
• Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis (2022, Cells)
• Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis (2012, PLOS One)

I wonder whether this MS-related research could relate to ME/LC. Conceivably that MS end-point might be a genetically or otherwise determined fork in the road (maybe depending on things like HLA or the specific HERV), where an alternative result could be ME/CFS (or ALS or Parkinson's or glioblastoma etc).