Everything you always wanted to know about non-cytolytic enterovirus but were too afraid to ask

[Graham]

Yet more evidence that I am an oddball. I only read the entry at face value: an interesting description of what was thought to be happening in cells. I didn't assume that it necessarily was a cause of ME, nor that it necessarily caused anything specific to happen. But it is an interesting aspect, and any detective worth his or her salt would not ignore unusual circumstances when investigating a crime.

I used to read a bit about medical history – various attitudes and approaches that were deemed to be certainly true in the past. I think what struck me most was the confidence with which the medical profession in general made assertive statements about what could and could not be the case: typical examples are that foul air was causing malaria, and that bacteria could not possibly live in the stomach. A readiness to dismiss things that don't agree with whatever was current thinking is a profound weakness. Mind you, so is a readiness to assume that any abnormal finding, even of doubtful providence, is the ultimate cause.

To me, the entry came across as an interesting observation that may or may not turn out to be relevant, but which does tie in with observations that other folk interested in ME have made in the past. None of that is evidence for anything, but you never know when or how something like this may turn out to be involved.

 

[Jonathan Edwards]

Non-cytolytic enteroviral infections exist. This is not disputed (right?).

I am not a virologist and am not up to date on this but from what I know and see on the web I suspect that the answer is no, this is very much disputed. In fact it is, at least for humans, a dead idea. If you google non-cytolytic enterovirus almost all you get is stuff about ME - which is pretty much a tell tale sign that nobody else actually believes in it.

There is no doubt that virus components hang around in tissues. Herpes is a good example. Enterovirus may hang around. But to call that 'infection' is a loaded term and I suspect that most virologists do not consider 'non-cytolytic enterovirus infection' a meaningful term. The Wikipedia entry refers across to ME! It has comments about virus being found in myositis and ALS etc. I don't see other sites mentioning that.

The myositis story I know about and I suspect it is typical. Around 1988-90 a set of samples from David Isenberg were studied and the authors thought they found enterovirus RNA. Then Victor Dubowitz reported finding the same. Now, David Isenberg's office for twenty years was next to mine and opposite Jo Cambridge's. Victor Dubowitz supervised Jo Cambridge's PhD which was on the possible role enterovirus in dermatomyositis. So we were kind of right in the middle of all this. In 1994 Paul Plotz, who is a close friend of all the above people, including me, because we are both birdwatchers, and was for a time head of NIAMS, looked carefully and found nothing. As far as I am concerned everyone mentioned accepted that the signal for enterovirus that had been reported was an artefact. I strongly suspect the same applies to the other conditions. So any page on this should say that although there are papers reporting enterovrus in these conditions the people who wrote those papers now realise that the findings were spurious.

This is what gets missed from write ups by people who are not actually experts in the field. If you look at the scientific literature you find all sorts of stuff that everyone has forgotten for very good reasons.

 

[Graham]

This is what gets missed from write ups by people who are not actually experts in the field.

The problem is though, Jonathan, that people like Wessely, Sharpe, White, (Chalder?) are regarded as experts in their field, and apart from you and a handful of others, who else in the UK medical or research world is there to challenge them? There comes a point when, in covering up the ineptitude of fellow members, or at best choosing not to get involved, it gets difficult for outsiders to trust any expert point of view.

One of the problems here is that we are operating at the full depth of our "knowledge". From what I can see, our understanding of things in the world only seem to reach high quality when our operating levels are at least one step beyond

Now we know you, and over time here you have interacted with us (and on our behalf), so we know to value your judgement. So in no way am I refuting what you say. But I would be very reluctant now to take any unknown professional medic's word for anything: now I always want back-up evidence. The problem is, of course, that I know so little. The pressure is to bow down before those who claim to know more. The PACE trial taught me not to be so stupid.

 

[JenB]

I am not a virologist and am not up to date on this but from what I know and see on the web I suspect that the answer is no, this is very much disputed. In fact it is, at least for humans, a dead idea. If you google non-cytolytic enterovirus almost all you get is stuff about ME - which is pretty much a tell tale sign that nobody else actually believes in it.

Wait, but @Hip's piece references studies in numerous conditions + animal models. It's a shame, because unless someone reports negative findings, all we have to go on are anecdotes like the one you describe.

 

[JenB]

And then there are also studies like these, which to me look like more basic virology, and have nothing to do with ME:

https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-8-473
https://www.ncbi.nlm.nih.gov/pubmed/20375176

I do think you'd need to do a deeper study before really being able to say. Especially research post 80s/90s. Or at least, I'd appreciate you explaining why the studies on non-cytolytic enteroviruses are all wrong. (Stopping short of any claim re: it's role in disease pathology.) I'm a bit confused, honestly.

(And I added the word "infection." Perhaps I should have said, "don't we know that enteroviruses can mutate and take on a non-cytolytic form?" The answer seems very clearly to be yes.)

 

[Lisa108]

If you look at the scientific literature you find all sorts of stuff that everyone has forgotten for very good reasons.

Some "stuff" might be forgotten for very good reasons. I'd wish the BPS-bubble would fall into neglect! Other "stuff" might be unjustly forgotten, because at some point in history there was no evidence, no technique to prove its validity. But science is in constant development. New techniques might prove that what was thought to not exist.

How many law suits were retrialed when the new technique of dna profiling was invented? That was only possible because the traces that were found were archived. Not forgotten.

I'd rather see a hypotheses being proven wrong over and over again by the newest standard of knowledge than to be wrongly dismissed at one point. (Though the best thing would be to prove it wrong by showing how it really works!)

Bad brainfog day, so please excuse my poor language skills today!

 

[Hip]

This is what gets missed from write ups by people who are not actually experts in the field.

That is very true, and for that very reason, I intend to ask a few virologists who are experts in non-cytolytic enterovirus if they would kindly take a look at the article, and point out any errors or embarrassing naiveties that it may contain. Only after such expert scrutiny would I feel confident that the article accurately represents the state of play in this field.

I strongly suspect the same applies to the other conditions. So any page on this should say that although there are papers reporting enterovrus in these conditions the people who wrote those papers now realise that the findings were spurious.

An up-to-date study on non-cytolytic enterovirus is this 2017 paper by Lévêque; if you look at the discussion section, it gives a sort of brief review of the field. No mention about the original findings being spurious.

If you google non-cytolytic enterovirus almost all you get is stuff about ME - which is pretty much a tell tale sign that nobody else actually believes in it.

One of the main thrusts of non-cytolytic enterovirus research is in chronic myocarditis and dilated cardiomyopathy. From what I have read, there does not seem to be any dispute about the persistent presence of this defective virus in the heart tissues in these conditions, though there is controversy about whether this virus causes these conditions.

There is also a proposed mechanism of how non-cytolytic enterovirus may cause the pathophysiology of dilated cardiomyopathy, namely that the enterovirus 2A protein these infections produce causes it. In mice, 2A alone has been shown to cause dilated cardiomyopathy.

But to call that 'infection' is a loaded term and I suspect that most virologists do not consider 'non-cytolytic enterovirus infection' a meaningful term.

Non-cytolytic enterovirus is actively generating viral proteins in the tissues, and appears able to replicate and propagate, so it looks like an active infection, albeit a slow, low level one. Non-cytolytic enterovirus is not like viral latency, where the virus does nothing at all in the deepest latency states.

So any page on this should say that although there are papers reporting enterovrus in these conditions the people who wrote those papers now realise that the findings were spurious.

I shall certainly add to the article the negative studies on myositis you mentioned elsewhere (though those negative papers could be flawed, due to the PCR primers used, which I will mention in the note). Or it might be better to remove the myositis reference entirely. I'll have to look into it more. Thanks for pointing those studies out.

 

[JaimeS]

I know some people say "Nah, that enterovirus theory ain't gonna work", but that's not really saying anything. A skeptical argument against needs to be just as well constructed and engaged in the details as the pro argument for.

An automatic no without examination is just as illogical as an automatic yes without examination.

Disbelief without examination is lazy thinking.

 

[Robert 1973]

I’m not qualified to comment on the accuracy but it seems to be well written and reasonably easy for the lay reader to understand.

Typo/grammaratical suggestions:

Several researchers, including Prof Nora Chapman, Prof Steven Tracy and Dr John Chia, theorize that it is specifically the non-cytolytic form of enterovirus infection that may cause ME/CFS. Persistent enterovirus is also being investigated as a possible cause for the other above-listed diseases [delete “as well” – repetition of “also”)].

Sorry, I’m not yet registered on MEpedia or I would have made these suggests there.

To me “enterovirus” looks strange without an indefinite article or being pluralised but I’m assuming this is the convention.

I’ve not finished reading it yet, so may add some more suggestions later.

Thanks for all the work you’ve put into writing it @Hip.

 

[Hip]

Typo/grammaratical suggestions:

Thanks Robert, typos and grammatical errors are useful to have pointed out. I'll make the corrections shortly.

There do appear to be some conventions used when referring to viruses. In the literature you sometimes see phrases such as "it is common to find virus in the tissues", instead of viruses or viral infection.

In the phrase above, "it is specifically the non-cytolytic form of enterovirus infection", I guess strictly speaking it should read "enteroviral infection".

 

[Hip]

I am wondering if this is your leading theory for whats going on in CFS?

I find all theories of ME/CFS interesting, but the enteroviral theory is the oldest and original one, and probably the most developed theory. I am also partial to any theories about immune dysfunction in ME/CFS, such as the immune priming theory. Theories don't necessarily have to be mutually exclusive either. I had one idea that a persistent low-level enterovirus infection along with immune priming might be the cause of ME/CFS (see here, here and here).

 

[Jonathan Edwards]

The problem is though, Jonathan, that people like Wessely, Sharpe, White, (Chalder?) are regarded as experts in their field, and apart from you and a handful of others, who else in the UK medical or research world is there to challenge them?

There is no guarantee that even 'experts' are in fat expert, but the point I was making was that if people try to reconstruct the body of knowledge in a field from the literature without firsthand experience of working in the field they are likely to miss the reasons why a lot of that literature is now considered obsolete.

 

[Jonathan Edwards]

Wait, but @Hip's piece references studies in numerous conditions + animal models. It's a shame, because unless someone reports negative findings, all we have to go on are anecdotes like the one you describe.

@JenB. I realise that for people who have not been in a scientific field for a decade or more this may seem surprising but it is generally accepted in clinical medical research that 90% of what gets published turns out to be dross. Either the findings are artefacts or they do not have the significance the authors hope they have at the time.

If you are not aware of this, you need to be. Otherwise MEpedia will become a graveyard of dead theories.

When I first started out in research I thought people should publish findings that negate the misleading studies in the field. I thought we should debate in the literature why interpretations were wrong. But I rapidly learned that this is considered bad form in science. The protocol is not to prove someone else's work was wrong or misleading, but simply to replace it by new work that says something more interesting.

Poor science does get torn to pieces in journal clubs in academic units. That is where we learn what is good and what is bad. All clinical trainees are exposed to that sort of critique every week for five years or more. But it is never mentioned in the literature.

What I describe was not an anecdote. In fact in this case Plotz repeated the work properly and showed that there was nothing to find. The French group gave possible explanation why the previous studies got artefacts - things like mast cell staining, which would show up in the inflamed tissue. Around that time most of us in the lab were doing our first DNA/RNA analysis studies and getting similar artefacts. It all made sense and we moved on.

 

[Jonathan Edwards]

And then there are also studies like these, which to me look like more basic virology, and have nothing to do with ME:

https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-8-473
https://www.ncbi.nlm.nih.gov/pubmed/20375176

And they have nothing to do with non-cytolytic enterovirus as far as I can see. They are studies of cytolytic effects of enteroviruses in cell lines. As far as we know enteroviruses are bad for us because they are cytolytic. What I doubt has any validity is the idea that there are unusual sorts of enterovirus that are bad yet not cytolytic. I may be wrong but I don't think there is anything in the ME media page that provides any reason to think there is.

 

[sb4]

@Hip I was wandering if you could fill in my peasant tier knowledge on the immune system? In your article you say that when the 5th primed from the end of the RNA gets deleted it allows the virus to avoid immune detection, why?

I understand that presenter cells show bits of protein (which contain unique amino acid sequences) to the immune system which basically checks that it's not on it's white list then attacks. I presume there is a similar system for DNA and RNA, so why doesn't it just detect the mutated virus as a new virus and attack it?

 

[Jonathan Edwards]

An up-to-date study on non-cytolytic enterovirus is this 2017 paper by Lévêque; if you look at the discussion section, it gives a sort of brief review of the field. No mention about the original findings being spurious.

This is a case report, with background review, relating to coxsackie cardiomyopathy. That is the one situation where, as far as I know coxsackie is of major clinical significance in the adult. The persistence of retrievable viral material in this situation is not surprising. But the word 'non-cytolytic' does not occur in the text. As far as I can see from a quick reading they have one case with an RNA mutation that blocks RNA replication in cell cultures. That would mean that any remaining viralRNA could not multiply. I amanita clear how that can explain persistence of virus and it would certainly not be a situation of persistent replication without cytolysis.

I intend to ask a few virologists who are experts in non-cytolytic enterovirus

I would suggest asking some virologists with a broad knowledge. My impression of the 'non-cytolytic enterovirus' story is that it is was a speculation by one or more individuals that was never taken seriously in the field because it does not add up. So if there are 'experts in non-cytolytic enterovirus' they are rather likely to be the few individuals who cling to the idea rather than actual experts in the relevant virology.

An automatic no without examination is just as illogical as an automatic yes without examination.

Disbelief without examination is lazy thinking.

Nobody is saying no without examination here. @JaimeS. I have been reading the stuff about 'non-cytolytic infection' ever since I started going to ME meetings and have never been able to find a coherent story in it. On one occasion Dr Chia came to IiME and presented his view. As a scientist I could not detect a coherent thread in his interpretation of the evidence. It is too long ago to remember the details but I was not surprised. I have the same feeling about a large proportion of presentations at medical meetings these days. People ignore basic biological factors that mean that you cannot string together a lot of observations that might superficially lead to a conclusion.

 

[Jonathan Edwards]

Non-cytolytic enterovirus is actively generating viral proteins in the tissues, and appears able to replicate and propagate

But the 2017 paper says the RNA cannot replicate, doesn't it?

 

[Jonathan Edwards]

the enteroviral theory is the oldest and original one

Yes. Some of the discussions around Ramsay's and Acheson's accounts came up in another thread and I found it interesting to read the paper by Acheson where he proposes that ME might be an atypical enterovirus infection. He based this on the assumption that patients had a paralytic disorder,as in polio.

However, it snow clear to everyone that nobody with ME has paralysis in any way like polio. The paralysis of polio affects specific muscle groups in a neuroanatomical pattern. People with ME have problems using muscles but there is no evidence of a motor neuron defect, so there is no biological similarity. Moreover, their problems do not show specific neuroanatomical patterns.

So Acheson's original reason for suspecting an enterovirus was spurious. For sure, it seems that a virus triggered the epidemics of ME, but no reason to think enterovirus.

 

[chrisb]

@Jonathan Edwards have you, I wonder, read Jenkins' excellent Introduction in Post -viral Fatigue Syndrome eds Jenkins/Mowbray, which libraries appear to be disposing of. She includes details of the LA outbreak by John Wilson and Pierre Walker read to a meeting in 1935.

It is a pity that do not have this in the site library as it is a worthwhile overview-and by a psychiatrist, who never mentions illness beliefs.

 

[Jonathan Edwards]

@Jonathan Edwards have you, I wonder, read Jenkins' excellent Introduction in Post -viral Fatigue Syndrome eds Jenkins/Mowbray, which libraries appear to be disposing of. She includes details of the LA outbreak by John Wilson and Pierre Walker read to a meeting in 1935.

It is a pity that do not have this in the site library as it is a worthwhile overview-and by a psychiatrist, who never mentions illness beliefs.

No, I would be interested to see that. Was there a particular aspect of what is said that is relevant to the enterovirus idea?