It was good to hear from “John” again in the comments this morning. My head has been so completely in the clinical world since I wrote that post, that it’s hard for me to come back to it. I’d rather step back and take a look at the big picture. I’m sorry if it’s too loose for you John. I’m a doctor again. I don’t have the time that I did to read the pure science in exquisite detail trying to divine the truth from little bits and pieces of incomplete information. Not my job. Thanks for the input though, and may you never need my services:). Fortunately, the patient community still has a few friends in the scientific world and we will continue to rely on them to help us. Dr. Mikovits and I continue to “translate” for one another.
What if everybody was trying to figure out what is, instead of what isn’t? It is a public health emergency, though it is truly the proverbial closing the barn door when the horse is long gone. Pandora’s box is open for the duration. A retroviral etiology made sense almost two years ago when the Science paper was published, and it still makes sense. So whether XMRV is XMRV’s or HGRV’s or XMLV’s, and whether VP62 is or isn’t the same as XMRV, and which ones have or haven’t been fully sequenced… Einstein said, “If you can’t explain it simply, you don’t understand it well enough.” I’m not saying I understand more than a little, but what I do understand is pretty simple. So here goes, an hypothesis, without references this time. Most of it is referenced somewhere on this blog (which has a search feature on the sidebar).
People have written asking me to write a For Dummies post. For those of you not inclined towards the biological sciences, the following Wikipedia articles are background reading that help to put the rest of this post in context:
CellDNAProtein biosynthesisRetrovirusMitochondriaMitochondrial DNA
All organisms have a strategy for perpetuating themselves. Viruses are the simplest, carrying out their tasks by hi-jacking cellular machinery from the host. Retroviruses have a very efficient evolutionary strategy, inserting into the host genome. Simple animal retroviruses, in particular murine leukemia viruses, MLV’s or MuLV’s insert in places in the host DNA called CpG islands, start transcription sites, where they activate genes, presumably to create favorable conditions for them. They become endogenous when transmitted vertically. Endogenous means that the viral sequences are present in every cell in the body. Once endogenous, a retrovirus can be fully replicative or not. If not, it may still be able to generate viral proteins if activated, setting up a cycle of persistent immune activation as the body tries to deal with the foreign products. It may be measurable in the form of antibodies and sometimes antibodies are generated in response to self, producing the low level autoimmunity seen so commonly in this patient group.
The axiom we were taught that viruses don’t jump species turns out to be untrue. Simple animal retroviruses are infectious to human cells in tissue culture. Animal cells have been used to grow live attenuated virus since at least the early ’30s. The first paper reporting the use of yellow fever vaccine, attenuated in mice, was published in 1932. Vaccines were tested on nurses and doctors. The first outbreak of a disease similar to ours was at LA County Hospital in 1934. The first cases of autism were described in the early ’40s. Kanner’s earliest paper on “infantile autism” was published in 1946. It has been known for a very long time that there were animal retroviruses present in the cells used to produce vaccines, but the assumption was made that it was an insignificant risk compared to the good done by vaccinating.
In general, nature maintains a balance by killing off the weak organisms. There have probably always been a few ME patients, women with failure to thrive, “the vapors”, so the potential was there, the “jump” had already occurred, but then, we had to improve on Mother Nature. So we gave it an incredible leg up. Mainlined it into almost everybody. And not just one virus, but lots of them, some capable of recombining with each other, so that everybody’s infection is a little different. The result? An unbelievable increase in the incidence of all kinds of chronic diseases. Neuroimmune, autoimmune, genetic illness, cancer. It really hurts that I’m so old as to remember how different it was 35 years ago, when I was in medical school. I can actually remember being taught to do a review of systems when taking a history so as not to miss anything, generally expecting it to be negative. A negative review of systems is a relative rarity now, even in children.
Regardless of what is there precisely, with respect to viruses and pieces of viruses, there are generalizations that can be made about the common pathophysiology seen in animals and humans. In mice, similar viruses can produce neurodegeneration or cancer. The viruses that produce neurodegenerative disease cause inflammation, with vascular permeability in the central nervous system. Other MuLV’s cause lymphoproliferation and malignant transformation.
Take a look at the following table:
NIH publication. Increase in cancer incidence 1950-1989. Ries et al.
So where do the dots connect clinically for ME/CFS? Simply put…
1. Persistent immune activation due to foreign viral product fueling inflammation. This happens in HIV disease. The way their disease is playing out, with proper treatment, they die sooner of the usual things. That’s the way our disease plays out without treatment, since untreated the disease doesn’t kill you like HIV. Rather taking the more colorful symptoms out of it, the expectation is earlier onset of cardiovascular, neurodegenerative disease and cancer. Vascular permeability, as in the mouse models, fits. Leaky endothelial junctions in the brain, gut, elsewhere.
2. Symptoms consistent with inflammation in the brainstem and other structures in the CNS. In particular, most of the “mysterious” symptoms of the illness, that have confounded doctors for so long, can be tied anatomically to a strip of dorsal brainstem, which is housed in a tight bony canal and sensitive to any swelling. Structures in close proximity include the cranial nerve nuclei, carrying all the senses above the neck, the spinothalmic tract, carrying sensory information from below the neck to the brain, including pain and temperature sense, the reticular formation, controlling sleep and arousal, and relay nuclei for the autonomic nervous system, regulating all the involuntary functions of the body, including vascular stability and endocrine control. Nuclei in the brainstem are responsible for the production of neurotransmitters, norepinephrine (the locus coeruleus), serotonin (the raph nuclei), and dopamine (the substantia nigra), so dysfunction affects everything which is experiential. There is also a venous plexus that would be subject to compression, consistent with the recent findings that venous insufficiency, poor drainage, is common. The feeling of “brain swelling” that many report is probably accurate, like all the “crazy” sensations that patients describe. Structures in close anatomic proximity to this strip of tissue are the cerebellar peduncles, the amygdala, hippocampus and pituitary.
3. Gene activation. In addition to making viral proteins or particles, simple animal retroviruses turn on genes, which may be clinically important, depending upon the functional integrity of the gene in question. Certain genetic disorders, such as Marfan’s and Ehlers Danlos, and certain autoimmune disorders, such as Hashimoto’s thyroiditis and Sjogren’s, are certainly over-expressed in the patient group. Methylation is necessary for proviral latency and it is clear that many of us have genetic methylation defects. However, it’s not as simple as methylating, as it isn’t desirable to induce latency in tumor suppressor genes.
4. Lymphocyte abnormalities, proliferation, depletion, dysfunction. Currently a focus of my reading, including clonal expansion. Rather than butcher it, I’m going to hold off on this one for now.
5. Mitochondrial dysfunction. The mitochondria are the energy factories of cells. ATP, the energy currency of the body, is produced from glucose in an oxygen dependent chemical reaction. Aerobic metabolism is much more efficient than anaerobic metabolism, to which the body must convert when not enough oxygen is present. Oxygen gets into mitochondria by diffusion along a pressure gradient, needing to cross the mitochondrial membrane. The internal mitochondrial membrane contains phospholipids called cardiolipins, and anticardiolipins turn up on the list of associated auto-antibodies seen in ME/CFS. MtDNA (mitochondrial DNA) is a circular chromosome which is inherited from the mother, unlike the nuclear chromosomes which come from both parents, so mtDNA is not subject to genetic recombination. Maternal inheritance certainly fits the epidemiological picture. MtDNA maintains genetic integrity, so it would be a safe place for a retrovirus to stow aboard.
Andrew Mason MD, from the University of Alberta, has been publishing on a human beta retrovirus associated with PBC (Primary Biliary Cirrhosis). It is similar to MMTV (mouse mammary tumor virus), which was known as the “milk factor” before anybody knew what a retrovirus was. PBC is associated with an AMA (anti-mitochondrial antibody). In the following papers, he makes his argument for an HBRV (human beta retrovirus) and it all looks pretty congruent with our HGRV hypothesis, including his rationale for the use of antiretrovirals.
An excerpt from the last paper:
HBRV and the mitochondrial phenotype
Arguably, any causative agent linked to PBC should be associated with the aberrant expression of pyruvate dehydrogenase (PDC)-E2 on the cell surface of biliary epithelium and in lymphoid tis- sue, a highly specific PBC phenotype that is thought to lead to the formation of AMA. In vivo, HBRV is detected in PBC patient’s cells with aberrant PDC-E2 expression. In vitro, homogenized PBC patients’ lymph nodes, the conditioned supernatants containing HBRV and even pure MMTV have all been shown to trigger the mitochondrial phenotype in healthy biliary epithelium, whereas control lymph node homogenates and other viruses do not. Importantly, no in vivo patient data exist to link the mitochondrial phenotype with either bacteria or xenobiotics; indeed the idea of molecular mimicry has been circulating for over 50 years and never proven.
Of interest, betaretroviral infection has also been linked to the mitochondrial phenotype in several immunodeficient mouse models that spontaneously express AMA. For example, MMTV p27 capsid and gp52 envelope proteins have been detected in lymphoid tissues and biliary epithelium that also express aber- rant PDC-E2. Furthermore, we have found that the development of AMA mirrors anti-MMTV production. Indeed, MMTV has been shown to be central in triggering viral cholangitis in the NOD.c3c4 mouse model of PBC, as highly active antiretroviral therapy and MMTV neutralizing antibodies abrogate cholangitis. Of interest, NOD.c3c4 mice treated with lamivudine and zidovudine (Combivir) develop viral resistance with mutations in the YMDD region of the reverse transcriptase gene, similar to muta- tions found in hepatitis B virus or HIV occurring as a result of antiviral therapy.
Using the NOD.c3c4 mouse model with MMTV infection, how- ever, we have found that highly active antiretroviral therapy with Truvada and Kaletra is efficacious without the development of resistance. Recently, the same combination has been reported to normalize hepatic biochemistry in a PBC patient with HIV and HBRV co-infection. Accordingly, a randomized controlled trial with Truvada and Kaletra is planned to treat patients with PBC who are unresponsive to ursodeoxycholicacid (UDCA). Indeed, it is notable that clinical trials ultimately led to the recognition that H. pylori infection caused peptic ulcer disease and the proof that a viral association with PBC may be resolved in a similar fashion.
In summary, there are converging data to suggest a mechanistic link of betaretrovirus infection with the mitochondrial phenotype of PBC in co-culture studies and in a mouse model. However, we still lack firm patient data linking virus with disease. Accordingly, before we can endorse the argument that the evidence supports a viral aetiology for primary biliary cirrhosis, further studies will be required to definitively demonstrate integrations sites in diseased biliary epithelium and the serological reactivity to HBRV in the majority of patients with PBC.