Enteroviruses - revisited

[Hip]

@eljefe19 I think it is mainly just Dr Paul Cheney who thinks pulsing immunomodulators is important in order not to lose their effect. But I don't think this has been validated in any studies.

I seem to remember reading somewhere that some of the Russian interferon inducers stop working after a few days (but I can't seem to find where I read this now — so perhaps I mis-remembered, and am wrong about this). But if some immunomodulators do suffer from a loss of effect after a few days (ie, they stop inducing interferon after a few days), then that would suggest pulsing immunomodulators might be beneficial.

Andrographis paniculata and several other supplements may effectively further boost the effects of interferon via their STAT-3 inhibiting effect. STAT-3 blocks effects of interferon in the cell, so interferon will probably work better if you can reduce STAT-3. More info here. I may take some of these STAT-3 inhibitors when I trial interferon suppositories.

I am not sure about the benefits of either boosting or inhibiting interferon gamma. It probably depends on the virus you have. Interferon gamma is a type II interferon, and is also a Th1 cytokine (promotes the Th1 response). Whereas interferon alpha, beta and delta are type I interferons. There are plenty of supplements that boost interferon gamma (list here), and Andrographis paniculata inhibits interferon gamma.

Interestingly enough, if you look at Dr Chia's tests of different interferon combinations for treating ME/CFS, it was the interferon alpha/gamma combination that put a couple of patients into remission for the longest time (14 months of remission), whereas the interferon alpha/delta combination did not produce any such long lasting remissions (of course, this could just be a random coincidence, as this was a very small scale test).

So this perhaps hints that interferon gamma (or interferon gamma inducers) is useful to add to an interferon alpha protocol.

 

[eljefe19]

Great info Hip. I wonder, why does Andrographolide inhibit interferon gamma when it also inhibits STAT3. What is the practical effect?

 

[Hip]

I wonder, why does Andrographolide inhibit interferon gamma when it also inhibits STAT3. What is the practical effect?

It's just one of those things. Any compound will have dozens of different effects in the body; some of those effects may be beneficial for your purposes, other effects might work against your intended purposes.

Since interferon gamma is probably desirable for fighting ME/CFS viruses, andrographolide may not be the most appropriate STAT-3 inhibitor. Bupleurum herb may be a better choice for inhibiting STAT-3, especially as Bupleurum also induces interferon alpha and beta. Bupleurum is a common herb in the Chinese herbal repertoire. This study found that Bupleurum inhibits coxsackievirus B1 with a selectivity index of 17.34, which is a reasonable figure.

 

[eljefe19]

Do you have any idea whether interferon beta is beneficial for CFS? Halcyon seemed to think it wasn't

 

[Hip]

Do you have any idea whether interferon beta is beneficial for CFS? Halcyon seemed to think it wasn't

I think @halcyon is suggesting that interferon beta might promote viral persistence rather than viral clearance, based on the results of this 2015 study. It is something to bear in mind, and certainly I have not seen any research that used interferon beta for ME/CFS; interferon alpha is always used. So I would use interferon alpha as my first choice to fight enteroviruses.

Though that 2015 study only looked at the effects of interferon alpha and beta on lymphocytic choriomeningitis virus (LCMV), and found that interferon beta promoted persistence. So at this stage, it's not clear if those results will apply to other viruses.

A quick Google search reveals this study, which found that interferon beta therapy helps clear enteroviral or adenoviral infections of the heart muscle (myocarditis) — and such heart muscle infections are probably very similar to the chronic enteroviral skeletal muscle infections found in ME/CFS patients.

But it is a complicated siltation, because in coxsackievirus B myocarditis, it is known that there are also autoimmune responses present, with autoantibodies targeting and disabling the energy-producing mitochondria in the heart muscle cells, which possibly may make it harder for these cells to clear viruses, due to an energy shortage.

Interferon beta has a known anti-autoimmune effect (interferon beta is used in the autoimmune disease multiple sclerosis for this reason), so perhaps interferon beta helps clear such heart muscle infections via it's anti-autoimmune action. That's just pure speculation, though.

I don't think interferon beta treatment of ME/CFS has even been tried in any studies. Although @RYO on this forum did have interferon beta therapy for his ME/CFS, based on the interferon beta myocarditis research — see this post.

 

[eljefe19]

@Hip would it be safe to say that if interferon beta helps clear Coxsackie b myocarditis through anti-autoimmune action that it would also be anti-autoimmune in ME/CFS? My doctor proposed trying interferon beta. Do you have any idea if a suppository form exists for interferon beta ?

 

[Hip]

@Hip would it be safe to say that if interferon beta helps clear Coxsackie b myocarditis through anti-autoimmune action that it would also be anti-autoimmune in ME/CFS?

Neither would be safe to assume; I was just speculating about why interferon beta was found beneficial for coxsackievirus B myocarditis.

Though my hunch is that the same anti-mitochondrial autoantibodies found in coxsackievirus B myocarditis could well be at play in ME/CFS, and be in part responsible for the low energy state of ME/CFS. More about this hunch in this post.

I have not seen interferon beta suppositories, though pharmalad.com do a whole range of injectable interferons including alpha and beta, at very good prices compared to the West. They ship internationally. Search their website for "интерферон" (= interferon in Russian).

 

[halcyon]

Though that 2015 study only looked at the effects of interferon alpha and beta on lymphocytic choriomeningitis virus (LCMV), and found that interferon beta promoted persistence. So at this stage, it's not clear if those results will apply to other viruses.

As I mentioned, interferon beta decreases T cell activation, which is probably why it helps in MS. In ME, with a chronic tissue infection, I believe the last thing you want is a decrease in T cell activation. Again, interferon alpha and beta do use the same receptor, so on a cellular level they should both stimulate the same antiviral genes; the question is just what other effects does interferon beta have on regulation of immune cells. This is where one difference appears to be.

I'm beginning to believe that one issue underlying the inability to clear enterovirus in ME is functional T cell exhaustion. This is thought to be a protective state induced in T cells in the face of a persistent infection and it results in a stalemate between the virus and the immune system in order to protect the body from excessive inflammation and tissue damage. The good news is that it might be reversible; the bad news is that it is difficult to do so and it appears to become a homeostatic set point as long as the infection is present (and perhaps even after it's gone), so the body will fight to stay in and return to this state. This is known to occur in other chronic infections in humans and there is some evidence it's happening in ME.

 

[Hip]

It is interesting that in interferon alpha treatment of hepatitis C virus infection, 15% of the patients who did not respond to this treatment had antibodies which neutralize interferon alpha, which likely explains their non response. Ref: 1

And in the treatment of multiple sclerosis with interferon beta, 13% of patients eventually develop antibodies which neutralize interferon beta (typically appearing after 9 to 18 months of interferon beta therapy). Refs: 1 2

I wonder if this might explain why, when Dr Chia got good initial results in treating ME/CFS with interferon, a second round of interferon treatment on the same patient would sometimes no longer have any effect. Perhaps that might be due to the development of neutralizing antibodies to interferon.


I'd like to know how and why the immune system makes antibodies which target interferon. Is it through bacterial contamination of the injectable interferon? I know that occasionally with human growth hormone (HGH) injections, you can develop neutralizing antibodies to this hormone, and I read that this is more likely when there is a contamination with bacterial fragments in the HGH injection. Pharmaceutical HGH is made using bacteria (recombinant DNA technology), and I believe interferon is made the same way.

 

[eljefe19]

@Hip how's your plan to start a interferon regimen going?

I saw in another post that you have had multiple stacks you've cycled through. I'm curious what your NK and Mito stacks consisted of, as I'm currently trying to boost these.

 

[Hip]

Mitochondrial supplements: Boosting Mitochondria Increases Energy, Leads To Viral Clearance. See also the mitochondrial substrates talked about in this post, which Dr Myhill thinks are in short supply in Group A2 ME/CFS patients.

Natural killer cell function boosters here.

 

[RYO]

As mentioned in my previous posts interferon B was used in patient with presumed coxsackie myocarditis. Anecdotally, my personal 6 month trials with Betaseron resulted in modest improvements. However, the improvements lasted 6-8 months. I recently experienced my worst relapse after trial of SC immunoglubin.

In general I do not think interferons are a long term treatment option. Interferons are expensive and difficult to tolerate. In addition, I suspect most patients will eventually develop interferon NABs.

 

[Hip]

However, the improvements lasted 6-8 months.

That is interesting. I think that is in keeping with Dr Chia's findings on interferon treatment: he found that most patients relapsed within a few months, but some patients went on for 14 months before relapsing.

In addition, I suspect most patients will eventually develop interferon NABs.

I wonder if the interferon alpha suppositories that I will be experimenting with shortly will be less prone to triggering antibodies that neutralize interferon.

My guess is that the interferon neutralizing antibodies appear because of possible bacterial antigen contamination of the recombinant interferon, which is made using bacteria. But if you administer recombinant interferon rectally, perhaps your intestinal mucous membranes will stop these assumed bacterial antigens from entering your body.

 

[Hip]

D'oh. Brain fog strikes again.

I just remembered that I have high titers to coxsackievirus B4, and my understanding is that Dr Chia found interferon alpha does not have effect against CVB4. So my plan to try out interferon alpha suppositories is probably not going to work. It may work for other patients with different enteroviruses though.



@RYO, do you know much about this? I know you had high titers to CVB4. I am I right in thinking that interferon alpha does not work for CVB4?

Dr Chia in his presentation at the Invest in ME 2009 London Conference at timecode 42:31 says:

Interestingly enough, my son also has coxsackie B4, and for coxsackie B4, the antibody titer did not change at all, which is what I usually see using ribavirin and interferon; it is ineffective against coxsackie B4.

Dr Chia reiterates that interferon is not good for CVB4 in this post:

Patient: At what point does it make sense to try interferon alpha / gamma?

Dr Chia: Not good for CBV4

 

[RYO]

I have review study somewhere that described the mechanism of action of how interferon beta helps in coxsackie infections. I have not read anything other than Dr Chia's studies using interferon alpha and gamma.

I think it is important to clarify that I improved from a level 2-3 to 5-6 after taking betaseron. I have never achieved full remission with any therapy.

 

[eljefe19]

I have review study somewhere that described the mechanism of action of how interferon beta helps in coxsackie infections. I have not read anything other than Dr Chia's studies using interferon alpha and gamma.

I think it is important to clarify that I improved from a level 2-3 to 5-6 after taking betaseron. I have never achieved full remission with any therapy.

I've already been able to improve my condition about as much using Oxymatrine and a multitude of complimentary supplements. Wondering if inf beta might be able to bring me from a 5-6 to a 7-8. Food for thought. Have you tried Oxymatrine or Equilibrant?

 

[RYO]

Yes, I have tried taking oxymatrine and equilabrant. Unfortunately, I had minimal improvement. It is much more difficult to take betaseron. There can be significant side effects (injection site reaction, elevated LFTs, etc). Betaseron should only be taken under supervision of physician.

 

[eljefe19]

@Hip can you clear something up for me? Self hacked says that stat3 inhibition inhibits Th1 cytokines. If I'm taking Oxymatrine is this desirable? I guess no one really knows if the positive effects on endogenous interferon outweigh the reduction in Th1 cytokines.

 

[Hip]

@Hip can you clear something up for me? Self hacked says that stat3 inhibition inhibits Th1 cytokines. If I'm taking Oxymatrine is this desirable? I guess no one really knows if the positive effects on endogenous interferon outweigh the reduction in Th1 cytokines.

I did not know that STAT-3 inhibits Th1, but what you say I think is right: we don't know whether the (possible) positive benefits of inhibiting STAT-3 outweigh the (possible) negative effects of inhibiting Th1.

In any case, my idea of inhibiting STAT-3 in order to fight intracellular non-cytolytic enterovirus infections is not a proven one; I have not seen any studies trying this; it was just a speculative theoretical idea that occurred me while I was reading about the mechanism of action of interferon alpha in the cell, a mechanism which involves STAT-1 and STAT-3.

I then tried out my STAT-3 inhibiting idea out on myself as a guinea pig, in the hope that it might have had some spectacular antiviral effect; but in my short term tests of around 1 month, I did not observe any major benefits, although I did see some minor increases in energy, and also interestingly, the tired, heavy limbs feeling you get with ME/CFS (sometimes called "molasses limbs") completely disappeared while I was taking my STAT-3 inhibiting and STAT-1 boosting protocol.


Just came across this paper: The Complex Role of STAT3 in Viral Infections

 

[eljefe19]

@Hip Thanks for the quick response. I have basically been guinea pigging a stack that includes heavy influence from the lists you have written up over the years, including the Microglial activation inhibitors, NK cell boosters, Dopamine support, anti-viral meds and supplements (based on Dr. Chia's work as well), Th2>Th1 shifters, mitochondrial support, Pre-probiotics (I have bad IBS but its under control with these and Mesalamine), anti-anxiety, Nrf2 activators, and finally now have added Stat1 promoters and Stat3 inhibitors. According to selfhacked.com Stat3 inhibition inhibits both Th1 and Th17 cytokines. On top of all these, I've added gcmaf, and discovered that Serum Albumin (anti-EV7) is in undenatured whey protein powder. My positive enterovirus tests were Coxsackie A and EV7, also HHV-6 (Which I take Artesunate now). I have to say even though progress is slow, and my methods non-scientific, my energy levels and level of feeling like I have a flu are probably 50% improved. Unfortunately depression, anxiety, and irritability are all risen. I feel like I'm doing about all I can minus Rituximab and Interferon. I have to say that I am blessed to be able to afford any supplements or meds I need, and also owe you a debt of gratitude for all your hard work over the years.
By the way, have you ever tried Ibudilast? I am hoping that adding Ibudilast, which I just ordered, will cut through the remaining brain fog and fatigue.