The reason why antivirals like Valtrex and Valcyte take such a long time to work in ME/CFS (or don't work at all), according to Dr Martin Lerner

Hip

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When treating herpesvirus-associated ME/CFS with antivirals such as Valtrex and Valcyte, Dr Lerner's studies showed it takes a long time for benefits to appear, usually 3 or 4 months for the very first signs of improvements to materialize, and a year or more for the full benefits to manifest. And for many ME/CFS patients, improvements from antivirals may not appear at all (you have to be lucky for antivirals to work for you).

Dr Martin Lerner, who pioneered antiviral treatment for herpesvirus ME/CFS, had a theory to explain why antivirals work so slowly in ME/CFS, or may not work at all:

Dr Lerner theorized that ME/CFS is caused not by regular herpesvirus infections, but is caused by abortive herpesvirus infections (to be defined in a moment).

Lerner says that all current herpesvirus antiviral drugs (including Valtrex, Famvir, Valcyte, cidofovir and foscarnet) have no direct effect against abortive infections. So these drugs cannot directly tackle the infections that Dr Lerner thinks are the cause of herpesvirus-associated ME/CFS.

These antiviral drugs work fine for regular herpesvirus infections, but not for abortive infections.



How does an abortive infection differ from a regular infection? A regular viral infection is technically known as a productive infection. It's called productive because when the virus infects cells, it replicates inside those cells and produces thousands of copies of itself, thousands of new viral particles. A productive infection is the sort you get when you catch a cold or flu.

An abortive infection by contrast does not produce any new viral particles.

An abortive infection arises when a virus (like EBV, CMV or HHV-6) enters into a type of cell in which it is not able to reproduce, because the conditions in the cell are not right.

Viruses are not able to reproduce inside certain types of cell, because those cells do not possess the necessary cellular machinery to allow the virus to make new copies of itself. The body has many types of cell: inside some cell types a virus can reproduce, but inside other cell types, the conditions are not right for viral reproduction.

Cells which a virus can enter, and then reproduce, are called permissive cells. Cells which a virus can enter, but once inside cannot reproduce, are known as non-permissive cells.



When a virus enters a non-permissive cell, it produces an abortive infection, which does not create new viral particles. In abortive infections, the virus may remain inside the cell for a long time, constantly trying to reproduce, but always failing to do so.

Dr Lerner believed that ME/CFS was due to such abortive infections (he explains his theory is this paper). In ME/CFS patients, herpesviruses like EBV, CMV or HHV-6 would start of as a regular productive infection, but some of these viruses would go off and infect non-permissive cells, and in those cells create an abortive infection.

So in the body of herpesvirus ME/CFS patients, according to Lerner, there are two parallel infections going on at the same time: the productive herpesvirus infection, and the abortive herpesvirus infection.

Lerner says the productive infection constantly makes a small amount of new viral particles, and these new viral particles then re-seed and sustain the abortive infection, by infecting more non-permissive cells. So the abortive does not die out, because it is constantly being re-seeded by the productive infection.



The way to tackle abortive infections is not to address them directly, according to Lerner, because we don't have the drugs to do so. So instead we fight abortive infections indirectly, by targeting the productive side of the infection with antivirals.

Dr Lerner posits that by using antivirals, you can inhibit the productive infection, and that stops it from creating new viral particles which re-seed the abortive infection. So the abortive infection is starved of its reinforcements. Then you just have to wait for the immune system to slowly kill off the abortive infection over many, many months.

So this was Dr Lerner's explanation for why antivirals take such a long time to work in ME/CFS. It's a slow process to kill off the abortive infection in this indirect manner.

According to Lerner, if we developed some new antiviral drugs which would directly target abortive herpesvirus infections, you could cure herpesvirus ME/CFS in a matter of weeks.



How might abortive infections cause ME/CFS? In abortive infections, no new viral particles are produced in the cell; but nevertheless the infected cells are littered with the viral genes and viral proteins created by the virus during its attempts to reproduce.

The virus may remain inside a cell for a long time in abortive infections, constantly trying to reproduce, but always failing to do so. And always synthesizing viral genes and proteins in the infected cells.

These viral genes and proteins may cause cellular dysfunction, and they may also be packaged up into tiny exosomes (little spheres made of lipids) which are ejected into the bloodstream and travel to reach other cells. The purpose of exosomes is to transport and deliver their contents into other cells.

One protein made in herpesvirus abortive viral infections is deoxyuridine triphosphatase (dUTPase), and this can be transmitted cell to cell via exosome transport. This particular protein is known to induce symptoms like ME/CFS symptoms. And this protein was found in ME/CFS patients.

So herpesvirus ME/CFS may in part be caused by this dUTPase protein, which is constantly being produced by abortive herpesvirus infections, and may travel in exosomes to reach other cells.

One new dUTPase inhibitor drug in the pipeline is TAS-114, and perhaps potentially this might be beneficial for herpesvirus ME/CFS.



More info on Dr Lerner's abortive herpesvirus theory of ME/CFS can be found in this thread:
Dr Martin Lerner's abortive infection theory of ME/CFS.

Although Dr Lerner passed away in 2015, work on the abortive infection theory of ME/CFS (and other diseases) has been taken up by a research group in Ohio State University — see Cort's excellent article here.
 
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Hip

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This could be another subset then maybe?
As I understand it, according to Lerner's theory, herpesvirus ME/CFS in general is due to an abortive version of the herpesvirus infection.

There may be different subsets regarding which herpesvirus you have (EBV, cytomegalovirus and/or HHV-6), but in each case, Lerner proposed that these viruses create an abortive infection in your body, and it is that abortive infection which causes the ME/CFS.

Abortive infections are a very unusual beast, and have hardly been studied at all.

Of course, there is also enterovirus ME/CFS, which is a different thing again. But interestingly, the so-called non-cytolytic enterovirus infections found in enterovirus ME/CFS are quite similar in many respects to herpesvirus abortive infections. In both cases, these infections live inside human cells on a long-term basis.
 

sb4

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@Hip One thing that is confusing to me. It says that the are some non permisive infected cells and and some permisive infected cells that keep infecting the non permisive. Why doesn't the immune system kill off the permisive? Too small amount infected? Goes in to hybernation when immune system active?
 

Wishful

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The theory might fit the occasional localized epidemics observed: a strain that's particularly good at triggering abortive infections, but not competitive at spreading.

If the non-permissive cells involved in ME are a small clump of specialized brain cells, that could explain the rapid switching effect of temporary remissions: the drug or other factor would alter the rate of some RNA transcription or whatever that would get those cells operating properly again, at least for a short time.
 

Hip

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@Hip One thing that is confusing to me. It says that the are some non permisive infected cells and and some permisive infected cells that keep infecting the non permisive. Why doesn't the immune system kill off the permisive? Too small amount infected? Goes in to hybernation when immune system active?
That's a good question.

It may be, as you say, that the productive infection in permissive cells goes into a state of latency, in order to hide from the immune system. Herpesviruses are all capable of entering the state of latency within cells, when it's advantageous for their survival to do so.

Like for example herpes simplex cold sore around the mouth: this virus hides in a latent state for many months or years in cells around your lips, but then when it detects a transient weakness in immunity, it springs back to life, creating more viral particles. Then a cold sore appears.

So productive infections can use latency as a means to hide away for a while, in order to strategically come back and fight another day, when the immune system is a little weaker. When they come back from latency, they will make more viral particles, and these particles may go off to infect more non-permissive cells, thereby sustaining the abortive infection.
 
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Hip

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The theory might fit the occasional localized epidemics observed: a strain that's particularly good at triggering abortive infections, but not competitive at spreading.
Quite possibly.

I was thinking in terms of the dual-factor theory of ME/CFS (originally conceived by Erik Johnson): this is the idea that ME/CFS outbreaks are due to both a virus, in combination with some localized immunosuppressive environmental factor (like the immunotoxic cyanobacteria present at the Lake Tahoe ME/CFS outbreak) which weakens immunity, and may make it harder for the body to quickly bring an acute viral infection under control.

If the initial acute viral infection is not quickly brought under control, this perhaps gives more time and opportunity for the virus to infect many non-permissive cells, thereby creating a substantial abortive infection in the body tissues.

The acute productive infection is then cleared up by the immune system after some days, as per normal. But now the abortive infection remains, and it's that which creates ME/CFS, according to Dr Lerner's theory.



If the non-permissive cells involved in ME are a small clump of specialized brain cells, that could explain the rapid switching effect of temporary remissions: the drug or other factor would alter the rate of some RNA transcription or whatever that would get those cells operating properly again, at least for a short time.
That could well be the case.

Also, if the abortive infection exerts its ill effects by packaging pathogenic viral proteins into exosomes, which then get transported in the bloodstream to other cells, creating the symptoms of ME/CFS, any drug or substance that might temporarily thwart or disrupt exosome transport might lead to a temporary remission.


Incidentally, the fact that abortive infections package pathogenic viral proteins into exosomes links this abortive infection theory to the "something in the serum" findings observed by several ME/CFS researchers (Prusty, Davis, Fluge & Mella).
 
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Wishful

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any drug or substance that might temporarily thwart or disrupt exosome transport might lead to a temporary remission.
I like that concept. I'll keep it in mind.

One problem I have in understanding biology stuff is not having a good feel for rates at which things happen. A wiki article might show a static diagram of an exosome forming, but what's the rate? Are they popping out at a few per hour, or millions per second? Diagrams show glial cells as a certain shape, but in reality they're extending skinny threads and retracting them too fast to see, constantly. Mitochondria are known to link up into networks in certain circumstances, but is the timeframe hours or microseconds? It does make a big difference when trying to imagine what's going on.
 

Hip

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In terms of testing for the presence of abortive infections, Dr Lerner this 2011 paper says:

We propose that ME/CFS patients have nonpermissive herpesvirus (EBV, HCMV, HHV6) replication, expressing immediate-early (IE) gene products, which induce host cell dysregulation and host cell apoptosis.
So it is the immediate-early gene products which seem to be markers for abortive infection, according to Lerner.



In this 2010 paper, Dr Lerner talks about testing for abortive EBV infection, and he states:
Both D (diffuse) and R (restricted) components of EBV early antigen (EA) indicate abortive nonpermissive incomplete virus replication to about the first 50 early genes of sequential early and late genes in the cascade of the complete genome (Figure 1).
Dr Lerner's testing criteria for active EBV infection in ME/CFS is:

High antibody levels in the VCA IgM test and/or the EA IgG diffuse test. Ref: here.

If you are positive for EBV by these criteria, then according to Lerner you are a viable candidate for antiviral treatment (he would use Valtrex for ME/CFS patients who only have EBV, or Valcyte when they have EBV and/or other active herpesvirus infections like cytomegalovirus and HHV-6).



(Note that in his studies, Lerner refers to abortive infections as "nonpermissive infections", but strictly speaking, nonpermissive describes a cell type — a type of cell which when infected by a virus results in an abortive infection. So nonpermissive describes the cell, and abortive describes the infection in that cell. However, many other researchers seem to use "nonpermissive infection" to mean "abortive infection").
 
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heapsreal

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I cant recall if it was an opinion or a study or by who but recall ebv had a way of avoiding the immune system by somehow lower the body's interferon production which then liwers natural killer cell function. This could be another way herpes viruses can persist and possibly why low nk function is found in cfsers??
 
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Are the VCA IgM and the EA IgG diffuse tests the standardized tests/markers for EBV, or are they specialized in some way (i.e will my UK Dr test for these things when referring me for a standard EBV test)?
 

gbells

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I don't think Lerhner is right about abortive infections but I do think he's right about multiple viral infections of the same cells simultaneously. Normally viruses are specialized to attack certain cell types. However, in the case of lowered immunity (period during a viral infection before antibodies are generated-about a month, steroids) viruses can take advantage of the vulnerable cells and infect a wider variety of cell types. So in my history I had Epstein Barr virus infection then a HHV6 infection (followed by coxsackie virus). EBV didn't give me ME and eventually I didn't even have any detectable antibodies for it (which could support Lehrner's theory that other viruses interfere with its replication) however I have detectable antibodies for HHV6. So HHV6 is probably replicating and its infections would be checked if the antibody level is high enough to handle the virus production. If all of his theory were right there would be no HHV6 antibodies.
 

Hip

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Are the VCA IgM and the EA IgG diffuse tests the standardized tests/markers for EBV, or are they specialized in some way (i.e will my UK Dr test for these things when referring me for a standard EBV test)?
I am not entirely sure what sort of EBV tests a doctor will typically order. EBV is a bit more complicated than most viruses, as it has more antibody tests. Whereas most viruses have just two antibody tests, the IgM and IgG tests, EBV has six possible tests:

VCA IgM
VCA IgG
EA IgM
EA IgG
EBNA IgM
EBNA IgG

When I was tested at The Doctor's Laboratory London, they tested me for EA IgM, EA IgG and EBNA IgG. They did not test me for VCA.
 
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When I was tested at The Doctor's Laboratory London, they tested me for EA IgM, EA IgG and EBNA IgG. They did not test me for VCA.
are these tests you had typically enough for one to choose to try antivirals? on a side note, is the Doctors Lab London preferred over tests done through Genova Labs? I live in London and understand Genova Labs are available to me here, and perhaps cheaper.
 

Hip

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are these tests you had typically enough for one to choose to try antivirals?
The normal battery of viral tests ME/CFS doctors use include coxsackievirus B, echovirus, EBV, CMV, HHV-6, parvovirus B19 and Chlamydia pneumoniae. The first two are not available in the UK. These tests, and labs which offer them, are detailed in my mini roadmap.


is the Doctors Lab London preferred over tests done through Genova Labs?
I don't think Genova do much in terms of viral tests.