When I started writing this blog, I was a very sick patient and the mother of a very sick patient, who had been neglected and abused by the medical profession. I made our experiences about trying to treat the disease public, because it was the only way I could be of service. Helping helps, and I was very much in need of help. Now I work for a non-profit dedicated to finding a cure for patients. I certainly don’t want the WPI to be hurt because I am controversial. I’m not really sure what to do about it, but keep restating that the WPI does not endorse my opinions and in my capacity as an administrator for them, I will not be telling other doctors how to treat their patients. But so many have written that it helps them for me to share my thoughts, that I will muddle through. There are an unbelievable number of people, isolated and without help. I’ve been there. I believe that my current understanding of the illness has and will result in finding ways to ameliorate the suffering, sooner rather than later. The scientific effort is desperately needed, because meaningful treatment options are so limited at this time.I would like to state publicly that I am personally grateful to any scientist working on XMRV. I really am sorry if my blog seems inflammatory, but I wish I could share my mail with the scientific community. In fact, scientists working on an illness should meet patients with that illness on a regular basis. Nobody is objective when you get right down to it. Everybody has an ax to grind. It is very sad that the issue is so politicized that the scientists and patients would feel at odds.I would like to restate that the words “cover up” used a couple of posts ago, referred to individuals who have been wrong, for example, people who encouraged psychiatric explanations for the disease, epidemiologists who didn’t study the right things, perhaps people who said that endogenous animal retroviruses in tissue culture couldn’t harm humans. Lots of reasons for individuals to be upset about how things are turning out and humans are, well human. They don’t like to be wrong. Cover up, consciously or unconsciously, is a normal human response to having been seriously wrong with unimaginably horrible consequences.Non-scientists discussing the science resembles two English speakers trying to communicate in Chinese. But there seems to be so little dialog about why the patients are sick, that it has become necessary for lay people to try to second guess the science, even without fluency in the language. The scientists are as isolated as the patients. They don’t share, because of fear of having work stolen, intellectual property issues and who is going to get the Nobel Prize.

For me, as a doctor, the proof is in the pudding. A simple retroviral etiology explains the pathology perfectly. Antiretrovirals move the illness. Case closed. It’s a retrovirus stupid. On to treatment, while the scientists figure out the details, so we have a test, and then the drug companies will get interested. Where the infectious agents came from is not important anymore, unless it is still happening; hence my willingness to put a target on my back to open up the discussion about X related disease and vaccines.

It is an old discussion, one in which the autism community has been embroiled for a long time. But the scientific community has chosen to believe that all those mothers of autistic kids are deluded, and don’t really know how or when their kids got sick. That they had normal kids and, within a few days of a vaccination were never the same, is just coincidence. The literature about CFS and vaccines seems to consist of one negative paper; here is the sum total of literature I could find:

• Infection and vaccination in chronic fatigue syndrome: myth or reality? Appel
• Chronic fatigue syndrome with autoantibodies–the result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant. Nancy

There are, however, some very interesting papers in the Gulf War Illness literature:

• Vaccination alone or in combination with pyridostigmine promotes and prolongs activation of stress-activated kinases induced by stress in the mouse brain. Wang
• RNAs in the Sera of Persian Gulf War Veterans Have Segments Homologous to Chromosome 22q11.2. Urnovitz

Inflammation activates latent virus, as does the stress hormone cortisol. For me, the fact that the disease is activated by physical and emotional stress was obvious from the beginning, as it has been for many people. It is the reason why the assumption was made that the illness is psychogenic. The fact that animal retroviruses have GREs and HREs (glucocorticoid and hormone responsive elements) in their LTRs was one of the facts that clinched it for me. Huge clinical correlation. The findings on PTSD and sustained cortisol levels with brain damage to the amygdala and hippocampus come into play here for GWI and ME/CFS.

• Traumatic stress: effects on the brain. Bremner
• Biological factors of post-traumatic stress: neuroendocrine aspects. Birmes

Take a look at the vaccination schedule for military recruits, which includes Anthrax and Small Pox, if deployed to a place where there is a “biological threat”: Military vaccination schedule

The press has been calling me recently. Why are vaccines such a hot potato? The big response to the subject exposes it as a sacred cow. What’s so controversial about a doctor saying that there is a chance that an unnecessary intervention may be harming patients and that, until we know more, the intervention should be held for people at risk? The automaticity with which doctors have come to prescribe vaccines is medically incorrect. We need to look at where we are now, not where we were when we started vaccinating Polio, Small Pox or Diphtheria. At this juncture, in my opinion, each vaccination should be thought about by a physician, in the same way prescribing a drug is. You don’t give drugs in batches to everyone. You consider each prescription carefully, for that patient, at that moment. That’s what is expected for every other prescription. Why should physicians suspend disbelief for this one therapeutic modality? A doctor is not supposed to hurt anybody, except that if he hurts somebody with a vaccination, that’s OK? Even if he already knows that this person has an immune dysfunction that hasn’t been studied with respect to vaccines? The patient has to live with the damage forever. Something is really wrong here. Doctors should think about that individual patient before ordering the shot. It shouldn’t be automatic if the patient has a history of CFS. What is the risk of worsening the disease from the shot? Or causing it in a family member? Risk to the individual, not the society.

There is of course a long literature on vaccine safety. The argument mostly goes that vaccines are safe in terms of unanticipated infection, because a study of the vaccine in question failed to show transmission of anything unexpected in a small number of people. But absence of proof is not proof of absence.

• Lack of evidence of endogenous avian leukosis virus and endogenous avian retrovirus transmission to measles, mumps, and rubella vaccine recipients. Hussain
• Identification and Characterization of Avian Retroviruses in Chicken Embryo-Derived Yellow Fever Vaccines: Investigation of Transmission to Vaccine Recipients. Hussain

The literature is also filled with failure to identify adventitious virus.

• Contaminant viruses in two live virus vaccines produced in chick cells. Harris
• Human and animal vaccine contaminations. Pastoret
• Simian Virus 40 and Human Disease. Shah
• Viral Nucleic Acids in Live-Attenuated Vaccines: Detection of Minority Variants and an Adventitious Virus. Victoria
• Deep sequencing reveals viral vaccine contaminants. virology.ws

Some of the failure to figure out what’s true with respect to XMRV is about one trick ponies having an over-reliance on PCR. It’s pretty clear as an observer that a negative PCR study means nothing. I don’t understand how somebody can say that there is no association between a virus and a particular condition if they can’t find the virus at all. There have even been PCR tests brought to market with no validation in humans. Just because you can detect a clone in a lab doesn’t mean you can detect a virus in human blood, especially when it has become clear that blood is a difficult place to detect it without amplification. The macaques cleared it quickly from the blood. It reminds me of doctors who no longer know how to do a physical exam because of an over-reliance on tests.

As I said before, we need to see the full Paprotka paper, but couldn’t the same detection problems be at work here that scientists are having with respect to sorting out whether XMRV is there or not? Did they really show more than that the virus was amplified in the xenograft? It doesn’t prove where it originated. Even if they did correctly prove that this is where XMRV came from, it doesn’t disprove that it is loose in the population now. And it doesn’t say anything about whether or not there are other retroviruses infectious to humans, originally derived from endogenous animal retroviruses, possibly created in the lab by accident, and  around for a lot longer than 15 or 20 years. Here’s the paper about the creation of the CWR22 cell line from which 22Rv1 was derived. Note the use of testosterone which would amplify XMRV.
Xenografts of Primary Human Prostatic Carcinoma. Pretlow

The argument about whether the recombination event of 2 pre-XMRV sequences was unique or not seems to center around the improbability of throwing clones when DNA mixes. But we are talking about short sequences that may have preferences as to how they fit together, and many, many chances to succeed. Simple retroviruses recombine. The pre-sequences are in the soup, even contained within human endogenous retroviruses. The first of the following references seems very important to the discussion, so I’m including the abstract here in its entirety:

• J Biomed Sci. 2000 Mar-Apr;7(2):77-99.
  

  Genetic reassortment and patch repair by recombination in retroviruses.

  Mikkelsen JG, Pedersen FS.
  Department of Molecular and Structural Biology, University of Aarhus, Denmark.

  Abstract

  Retroviral particles contain a diploid RNA genome which serves as template for the synthesis of double-stranded DNA in a complex process guided by virus-encoded reverse transcriptase. The dimeric nature of the genome allows the proceeding polymerase to switch templates during copying of the copackaged RNA molecules, leading to the generation of recombinant proviruses that harbor genetic information derived from both parental RNAs. Template switching abilities of reverse transcriptase facilitate the development of mosaic retroviruses with altered functional properties and thereby contribute to the restoration and evolution of retroviruses facing altering selective forces of their environment. This review focuses on the genetic patchwork of retroviruses and how mixing of sequence patches by recombination may lead to repair in terms of re-established replication and facilitate increased viral fitness, enhanced pathogenic potential, and altered virus tropisms. Endogenous retroelements represent an affluent source of functional viral sequences which may hitchhike with virions and serve as sequence donors in patch repair. We describe here the involvement of endogenous viruses in genetic reassortment and patch repair and review important examples derived from cell culture and animal studies. Moreover, we discuss how the patch repair phenomenon may challenge both safe usage of retrovirus-based gene vehicles in human gene therapy and the use of animal organs as xenografts in humans. Finally, the ongoing mixing of distinct human immunodeficiency virus strains and its implications for antiviral treatment is discussed.

• Generation of diversity in retroviruses. Katz
• High prevalence of an IgG response against murine leukemia virus (MLV) in patients with psoriasis. Molès
• Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses. Christensen 

Here is an excellent review article about HERVs, written in 1996, by Urnovitz, an author of the GWI paper above about RNA in the sera of GWI subjects:
Human endogenous retroviruses: nature, occurrence, and clinical implications in human disease. Urnovitz
I thought this passage particularly fascinating in light of what we observe with respect to viral triggers leading to long standing morbidity and the presence of activated viruses, such as EBV, HHV-6 and CMV:

With the development of primary cell culture techniques it became possible to analyze virus-cell genome interactions. For example, when low doses of the Bryan high-titer strain of Rous sarcoma virus (RSV) were used to transform primary chicken embryo cells, such transformed cells failed to produce detectable quantities of virus unless exposed to super- infection by an unrelated avian virus. When this was done, the cells produced significant amounts of RSV-like particles. Ultimately, it was shown that the original RSV nonproducer (NP) cells carried a defective endogenous virus that required superinfection by ‘‘helper’’ virus to permit a full cycle of endogenous virus replication. Endogenously produced virus (RSV-0), defective in replication, was detected in NP cells by DNA hybridization techniques. In some cases, infectious virus was inducible from NP cells by chemical or physical inducing agents.

The described results are relevant in attempts to detect HERVs: they document that a defective endogenous retrovirus genome can be expressed if missing gene functions are provided by a suitable superinfecting helper virus, i.e., a phenomenon known as complementation; that a defective endogenous virus can be induced by a physical agent such as X-irradiation or chemical agents such as the halogenated pyrimidines; that the induced endogenous virus may form pseudotypes with the helper virus to yield progeny with a new, albeit temporary, host range; and that the events described may be only temporary or spasmodic. However, if such events occur in vivo, they may suffice to elicit antibodies to viral agents that otherwise might go undetected.

And this about HERVs containing murine sequences: 

HERV 4.1 (HERV-E): Multicopy Type C
Martin and coworkers used as a probe a 2.75-kb seg- ment of African green monkey DNA that hybridized to murine leukemia virus (MuLV; AKR mouse ecotropic leukemia virus) and endogenous baboon virus (BaEV). The described probe detected related sequences in human brain fragments and in a human DNA library. Clone 4.1 made up a full-length provirus. The related clone 51.1 approximated a retroposon. The complete nucleotide sequence of HERV 4.1 was determined. The 3ï¿¿ LTR is 449 bp and the 5ï¿¿ LTR is 495 bp, with 95% homology between them. Genomic DNA consisted of 8,806 bp organized into gag, pol, and env sequences interspersed between the two LTRs. On the basis of deduced amino acid sequences, HERV 4.1 gag-pol sequences exhibited approximately 40% homology to Moloney MuLV. Termination codons and point deletions in the genome indicated that HERV 4.1 was replication defective. However, long ORFs in the pol and env regions suggest that they might be expressed. The fact that the 18-bp primer binding site for tRNA does not match tRNAPro (found in most mammalian type C retroviruses), but is homologous to tRNA glutamine, is unusual and has suggested a primordial origin of HERV 4.1.

The diversity of the RTVL-H family is further illustrated by the report of Hirose et al. cDNA libraries were prepared from poly(Aï¿¿) RNA obtained from various tissues and cell lines by using oligo(dT)- or tRNAHis-derived oligonucleotide primers. PCR was used for amplification with appropriate primers. Several RTVL-H clones containing env-related se- quences were isolated. One clone (RGH 2) approximated a provirus in size (8.7 kb in length), with both 3ï¿¿ and 5ï¿¿ LTRs. The env gene had an ORF capable of encoding 570 amino acid residues. Comparison of the deduced amino acid sequence of the env region of clone SA49 with the immunosuppressive peptide regions (p15E) of various conventional retroviruses revealed homologies of 75 and 71.2% for Mason-Pfizer monkey virus (type D) and reticuloendotheliosis-associated virus (type C), respectively, and ca. 58% homology to both feline leukemia virus and Moloney MuLV. Thus, HERV SA49 is a mosaic of sequences related to both type C and D retroviruses.

Scientists have been playing with mixing animal and human cells in the lab for many decades now. Animal-Human Hybrids Spark Controversy.
Chimeric cells and whole animals have been and are being created. This is a new subject for me, but first blush reads like science fiction:

• Human x mouse somatic cell hybrid clone secreting immunoglobulins of both parental types. Schwaber
• Chimeric mice derived from human-mouse hybrid cells. Illmensee
• Pattern of Immunoglobulin Synthesis and Assembly in a Human-Mouse Somatic Cell Hybrid Clone. Schwaber
• Human lymphocyte-mouse myeloma somatic cell hybrids: selective hybrid formation. Schwaber

Again, it seems plausible, not in any way conspiracy theory or even wild conjecture, but a worthwhile hypothesis, that animal retroviruses have been finding their way into humans from the lab for a very long time. Questions supported by references. My concerns need to be addressed, not dismissed. After introduction, horizontal and vertical spread would have obscured the epidemiology, especially given the extremely long time period that can pass before activation of the infection. I have the impression from the only epidemiology I have available to me at this time, my mail, that there are peaks, both in patients’ current age and in the year when they became ill, that suggest something or somethings went out horizontally in a batch related fashion. This combined with the obvious family involvement, as documented repeatedly in the comments of this blog. To me, it is an epidemiologist’s dream. We need it studied.