Open Medicine Foundation blog post, 9 Sep 2016: Viruses and CFS: Statements by Ron Davis and Bob Naviaux
Question – Many ME/CFS experts have improved the symptoms in some patients by treating with antivirals and Ampligen (polyIC double stranded RNA). I think this proves that ongoing viral infections are causing our symptoms. It is not merely “tired patients” who are stuck in a lowered metabolic state because of a past trigger (which now is gone).
First of all, it is important that people actually read our paper first before drawing conclusions from news reports and blogs and criticizing something that we never said. I have seen a number of generalizations starting to appear in blogs and reports by journalists in even good newspapers and magazines that are starting to drift too
far afield from the actual science in our paper.
We devoted a section of the paper to this and related questions about infections. The section title was: “A Homogeneous Metabolic Response to Heterogeneous Triggers”.
It concluded with the sentence:
“Despite the heterogeneity of triggers, the cellular response to these environmental stressors in patients who developed CFS was homogeneous and statistically robust.”
As background for this conclusion, I recommend reading our paper on this topic entitled, “Metabolic features of the cell danger response” (PMID 23981537).
Second, many people do not understand that the first response our body mounts against a viral, bacterial, or any kind of infection is metabolic. Yes, our chemistry is our first line of defense. Our chemistry reflects our instantaneous state of health. Innate immunity is coordinated by mitochondria and is an essential first step in developing adaptive immunity to any infectious agent. Without innate immunity there can be no antibodies and no NK cell activation, no mast cell activation, and no T cell mediated immunity.
In addition, all antivirals have metabolic effects that have nothing to do with inhibiting viral DNA or RNA synthesis directly. Many antiviral drugs inhibit the key metabolic enzyme SAdenosylhomocysteine Hydrolase (SAHH).
Inhibition of SAHH causes an increase in intracellular SAH levels. SAH is a potent inhibitor of DNA, RNA, protein, and small molecule methylation. This affects both viral and host cell epigenetics, gene expression, mRNA translation, and protein stability.
The inhibition of methylation reactions in the cell also affects neurotransmitter (dopamine, norepinephrine, and serotonin) and phosphatidylcholine membrane lipid
synthesis, folate and B12 metabolism, and many other reactions. So by giving antivirals, doctors are not just inhibiting viruses, they are also inhibiting many host cell metabolic functions.
Sometimes the inhibition of host cell functions can attenuate ME/CFS symptoms for a time, but in other cases, using potent antiviral drugs inhibits mitochondrial and methylation reactions and can delay a full recovery from ME/CFS.
Ampligen is a form of double stranded RNA called poly(IC), for poly inosinic:cytosinic acid. We have studied the action of polyIC extensively and have published this in our studies of autism and virology. It acts by binding to an innate immune receptor called TLR3, creating a simulated viral infection.
If you expose a pregnant animal to a single dose of polyIC at the beginning of the second trimester, she develops a 24-hour flu-like illness then completely recovers. However, her pups have social and cognitive abnormalities similar to autism for life. If you look at their brains, you find that they have activated microglia and brain inflammation for life.
In adults, Ampligen also binds the TLR3 receptor, and activates an incomplete antiviral response characterized by a non-MyD88 dependent activation of interferon and
other cytokines. Long-term use of polyIC carries a risk for toxicity because of chronic innate immune stimulation. In certain clinical situations like cancer or Ebola virus infection, the toxicity is actually part of the therapeutic effect.
Chronic interferon release causes flu-like symptoms, and the inhibition of mitochondrial protein translation. This can lead to secondary mitochondrial dysfunction. As I noted in an earlier Q&A response, sometimes the inhibition of mitochondrial function can make some
people with ME/CFS feel better temporarily because some symptoms can come from unbalanced overactivity of some of the hundreds of functions mitochondria perform. However, in the long term, any pharmacologic inhibition of mitochondrial function will delay a full recovery.
Third, latent and reactivated viral and bacterial infections can occur, but in the case of ME/CFS that has lasted for more than 6 months, this may be the exception rather than the rule.
Some doctors and scientists have not done a good job at educating patients and other scientists about the difference between serological evidence of infection in the form of antibodies like IgM and IgG, and physical evidence of viral replication like PCR amplification of viral RNA or DNA, or bacterial DNA.
We have learned in our autism studies with Dr. Judy Van de Water that supertiters of antibodies do not mean new or reactivated viral replication. Supertiters of IgG antibodies mean that the balancing T-cell and NK cell mediated immune activity is decreased.
This is a functional kind of immune deficiency that causes an unbalanced increase in antibodies. This is like the famous figure-and-ground illusion that shows the silhouette of two faces that also create the form of a vase.
Both things happen. But which is cause and which is effect? Increased IgG antibodies to CMV, EBV, HHV6, Coxsackie, etc. are not good evidence of a reactivated viral infection. This can be proven in most cases by trying to measure viral DNA or RNA by PCR in the blood or swollen lymph nodes. In most cases, supertiters of IgG are PCRnegative. There
are exceptions to this generalization.
Chronic PCR surveillance studies in healthy humans are showing that little waves of viral replication happen periodically throughout our lives. We have been, and are regularly infected by hundreds of viruses over a lifetime.
Sometimes this is obvious and causes a symptom like blisters or an ulcer around the mouth. However, most of the time these waves of viral replication are silent and produce no symptoms at all because they are handled in the background by the innate and cell-mediated immune system.
Even the deadly poliovirus infected 150 to 1800 people, producing only mild or unnoticed infections, for every one person who developed paralytic disease.
In most of the cases of ME/CFS that I have seen where IgG antibody titers have been measured before, during, and after antiviral therapy, the antibody titers remain high after treatment, even though the patient may report symptomatic improvement.
I believe the symptomatic improvement after antiviral treatment may have more to do with the metabolic effects of antivirals in ME/CFS than their action on viral replication. The good news is that this hypothesis can be studied scientifically and put to the test easily using the tools of PCR and metabolomics.
Good science needs to remain open, ask the questions without bias, design good experiments, take careful measurements, then have the courage to follow the data wherever they may lead.