ERVs and Multiple Sclerosis

While Ive mentioned the connection between endogenous retroviruses and Multiple Sclerosis on teh blag before, I realized Ive never written a post on this topic. Fortunately I just read an interesting paper thats provided me with a good opportunity to do just that:

Analysis of transcribed human endogenous retrovirus W env loci clarifies the origin of multiple sclerosis-associated retrovirus env sequences

In addition to being ‘cancer’ viruses, it seems like another trick retroviruses are good at is screwing with our central nervous system. For example, HIV-1 infection leads to HIV associated dementia, and an effect of HTLV-1 infection is tropical spastic paraparesis (your myelin gets shredded).

Of course, other viruses can wreck havoc on your brain if they get in, this isnt specific to retroviruses (remember HSV-1?), but researchers have made a connection between retroviruses ability to demyelinate neurons, and the demyelination of neurons in multiple sclerosis patients, and endogenous retroviruses.

CAE had a neat post on this a while back, but basically, we can find HERV-W (a family of human ERVs) envelope proteins in MS patients lesions, but not in normal brains. Yay! An avenue to develop new treatments!

… But the HERV-W family used to be a gammaretrovirus.

There are lots of gammaretroviruses. Hell, the retrovirus killing off Koalas right now is a gamma.

How can we be certain that MS is associated with an endogenous retrovirus? How do we know MS isnt caused by a brand new infection by an exogenous retrovirus?

The HERV-W family is composed of about 650 elements. 280 of which contain some kind of gene, while the rest are just solo LTRs that have ‘popped out’ their coding sequence.

None of the remaining coding sequences can make a replication competent virus.

BUT! A handful of the coding sequences can make complete, or almost complete envelope proteins. One of these complete envs we know as ERVWE1, and under a different name, Syncytin-1– the protein that helps make placentas.

So there are only a few potential ‘complete-ish’ HERV-W envelope proteins that could be contributing to MS. If we find envelope mRNA that does NOT match up to theses few sequences perfectly… if we see a shitload of variation in these envelope sequences (a la HIV-1)… holy crap, there might be a ‘new’ retrovirus out there causing MS.

Happily (?) when Laufer et al sequenced the retroviral transcripts isolated from MS/nonMS patients, everything matched up to endogenous HERV-W genes, or combinations of them (half one HERV-W env, half another, etc). The ‘HERV-W’ protein we are seeing in the brains of MS patients is endogenous.

But Laufer and crew did find some odd things…

1– They used PBMC (blood immune cells), not astrocytes or glial cells… but they found HERV-W transcripts in both populations. OMFG JUNK RNA OH NOEZ!!! Yes, sometimes transcription is just noise. You have to look at protein levels, not just RNA levels, and this lab admittedly didnt.

2– Syncytin-1 is not the only HERV-W capable of coding a pretty-complete env. We assumed the protein present in MS patients lesions was Syncytin (leading to ‘WTF is placenta gene doing turned on in brains??), but its probably actually a different HERV-W env on the X chromosome, Xq22.3 (also found in chimpanzees. animal model! w00t!).

So dont worry, you arent going to get infected by with an ‘Multiple Sclerosis Virus’ from kissing someone or having sex without a condom. You were infected with the virus associated with MS tens of millions of years ago.

WHEW! lol.

Comments

  1. #1 Optimus Primate
    April 16, 2009

    I’ll probably have more questions the more I think about this, but the one that springs immediately to mind is this: does this knowledge make a cure for MS anytime soon seem more likely, less likely, or neither of the above?

  2. #2 tim
    April 16, 2009

    makes for a complicated way to view the disease, as it hasn’t been classified as “genetic” in the usual sense, and its rare to see a family history of MS.

    If we “all” have HERV-W ERV, then multiple factors must influence expression of HERV-W products, as well as other factors influencing individual response to those expressed products.

    t

  3. #3 Paper Hand
    April 16, 2009

    A general question about ERV’s – is this sort of thing typical? That is, do ERV’s simply slowly lose their infectibility and killability over time? Would our earliest ancestors infected with this virus have seen the occasional fully-infectious retrovirus popping out of the genome, and gradually it lost the ability to infect? Is it likely, then, that over the generations, the ERV will lose the ability to become active as well? (Which makes sense – if it loses the ability to infect, then it becomes beneficial to have a longer-lived host)

  4. #4 Magnus
    April 16, 2009

    They’re killing the koalas? Such an evil force is unheard of.

  5. #5 cprs
    April 16, 2009

    Fascinating – 26 pages of hard text nicely summarised.

    The chimp homologues/orthologues for a relatively young virus are interesting, and hints of physiological role for the ERVWE1 gene and the Xq22.3 HERV-W env element might add to the growing collection of functional as well as dysfunctional ERV elements, but the speculation is premature.

  6. #6 cprs
    April 16, 2009

    Relatively young? – Mol Cells. 2008 Jul 31;26(1):53-60.
    Perhaps not.

  7. #7 Jason Dick
    April 17, 2009

    Abby, why don’t you make use of the “Peer Review on Science Blogs” tag?

  8. #8 MitoScientist
    April 17, 2009

    So is the ERV becoming active in MS patients? And thus causing the disease? Something like that?

  9. #9 Sili
    April 18, 2009

    If it’s confined to the X chromosome, does that mean that MS is distributed unevenly between the sexes?

  10. #10 ERV
    April 18, 2009

    Optimus– Its just an ‘answer’. Maybe if it were an exogenous retrovirus, we could try antiretrovirals…

    PaperHand– Its actually rather odd that humans dont have a retrovirus that exists in exogenous and endogenous form (another reason scientists were wary about the MS virus being endogenous)– lots of other species do (eg MMTV).

    Jason– When BPR3 started it was super-serial. I am not a serious blagger, so I felt it was inappropriate for me to join their group. Now I might, but Im just not in the habit.

    Mito and Sili– Dunno. Active ERV proteins could be a cause of MS, an effect of the cause of MS, or an effect of a cause that ends up perpetuating MS. So even though the putative ERV gene is on X, what starts the production of the protein might not be on X, thus wouldnt be sex-linked.

    And its really hard to figure this all out because we all have the same ERVs (see tims comment, #2). Our lab is currently playing some scientific tricks with mice that lack certain ERVs to see what happens to them after we do our science magic (cancer, not MS). Ill update you all on what happens in like 3 years…

  11. #11 Craig E.
    April 18, 2009

    As having been (relatively) recently dx’d with RRMS, and coming from a strong biology, biochemistry, and microbiology background (spent 20 years as a Clinical Laboratory Technologist… a “MedTech”), I find the whole idea of the HERV’s utterly fascinating.
    Has anyone read Greg Bear’s “Darwin’s Radio”?

  12. #12 Paper Hand
    April 18, 2009

    Thanks for the reply, Abbie! There’s still a lot about ERV’s I find confusing, but I’m sure it’s too complex to describe in a brief comment. Do you have any recommendations for good books about the topic, at the level of a layman with a decent grasp of genetics and evolution?

  13. #13 W. Kevin Vicklund
    April 19, 2009

    Has anyone read Greg Bear’s “Darwin’s Radio”?

    Yeah. Blah. Suffered from Dan Brown Syndrome – take a neat scientific discovery and blow it out of proportion and any recognition, all while creating strawman stereotypes of the antagonists. Plus, at every scene change I spent half the scene trying to figure out what happened in the interim. Disjointed, implausible, and self-contradictory.

    Not a book I’d recommend, from an author I normally would recommend.

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