Monday, December 21, 2009

News on Important New Studies Underway

Since the initial findings of the link between XMRV and ME/CFS became public in October, a flurry of new research has ensued.  The study at the top of the list is currently underway at Uppsala University to try and replicate the findings of the Whitemore Peterson Institute in Swedish patients.  The study is very well organized, however it's findings could be a mixed blessing: XMRV findings may be different in European cohorts, meaning that other closely related retroviruses might be discovered if new studies are pursued.  Dr. Jonas Blomberg's real-time PCR assay might just be what is required to find these viruses.

Another study is currently underway to determine the atomic structure of XMRV protease at one center.  This study was initiated after a link was made to XMRV in certain prostate cancer cell lines.  Crystals of the protein have been grown, however this is only a first step: heavy metal derivatives must be produced, and crystals must be found that will diffract to a sufficient resolution to obtain useful data for drug development - a process that is still months away.

Another study is currently getting underway at Cornell University that will seek to determine retroviral diversity in ME/CFS patients, and try and correlate the findings with functional status in CFS patients.  The project is being done in collaboration with the Whitemore-Peterson Institute and the Columbia University Center for Infection and Immunity.

Another study is getting underway at Instituto de Biologia Molecular en Medicina y Terapia Genica, Universidad de Guadalajara to determine if infecting peripheral monocyte cell lines in culture with XMRV alters the 2-5A synthethase/RNASE L pathway, and the resulting differential cytokine expression.  I don't understand spanish, so it would be appreciated if someone who does could dig up more information for me!

Fellow Britons Unite For The Truth!

It has come to my attention as of late that our government holds a file in the National Archives at Kew, which contains MRC documentation on ME since 1988.  The file was to be kept from the public eye until 2023, however this has been extended until 2071!  Normally, such measures are only enacted on matters of defence, national security, and in matters that are considered very confidential.  But what on earth would the medical research council want to keep from public view???  It comes from the same time as the UK's own version of Dr. Reeves - Simon Wessely began to propagandize ME as a psychiatric illness.  It would seem rather absurd to even cite patient confidentiality, as a black marker would make short work of maintaining patient confidentiality.

However, fellow Britons, you have options.  In THIS document, there is a LINK to request a review of the record under the Freedom of Information act, which requires the filling out of only a few fields.  If the National Archives does not provide a satisfactory response, then contact the parliamentary and health services ombudsman:

The Parliamentary and Health Service Ombudsman
Millbank Tower
London, SW1P 4QP
Telephone: +44 (0) 84 5015 4033
Fax: +44 (0) 20 7217 4000

You may also want to contact:

Secretary of State for Justice and Lord Chancellor
Selborne House
54-60 Victoria Street
London SW1E 6WQ

Also, if the requested information is refused, an application may be made to the Information Commissioner, who has the power to order such disclosure, and if unsuccessful, the applicant may appeal the decision to an appeal tribunal - in many cases which have been successful the information has been provided with some redactions to protect confidentiality: The appeal tribunal consists of experienced barristers or solicitors which must provide a fair and independent review.  It is your right, and I strongly recommend that you exercise these rights!

Tuesday, December 8, 2009

Male CFS Patients May Have Option

In recent studies, it has been shown that DHT (dihydrotestosterone) increases XMRV replication rate threefold.  This is not surprising, considering that a number of prostate drugs target this very hormone.  Testosterone is metabolized to DHT, which is more powerful - but it is also implicated in pattern baldness, prostate problems, and excess body hair.  Some drugs such as Casodex and Flutamide will block DHT at its receptor, however they will result in impaired fertility, loss of libido, and feminization effects, as testosterone is necessary to mitigate the effects of estrogen.

On the other hand, blocking the conversion of Testosterone to DHT should result in a significant drop in viral replication rate.  There are 2 very safe drugs that I can think of that can attain this effect: Avodart (dutasteride), and Proscar (available as Propecia in a lower dosage form).  A threefold drop in viral replication rate could have a significant effect on symptoms of ME/CFS - It is my opinion that at a certain threshold, the immune system is capable of keeping XMRV in check, hence why XMRV is found in a small number of healthy controls.  I would like to see a clinical trial enrolling male patients to test this hypothesis.  The effects of these drugs have negligible effects on male fertility - treatment will only produce mild reductions in sperm count averaging 6%.  Serum testosterone increased considerably, which is necessary for muscle protein synthesis, regulating the hypothalamus-pituitary axis, and increasing mental and physical energy - all things ME/CFS, Fibromyalgia, and Gulf War Syndrome patients could stand to benefit from.

Monday, December 7, 2009

CDC Damage Control: ME/CFS Research Group Relieved of Duties

In a stunning move, responsibility for XMRV research has been taken away from the ME/CFS working group within the CDC, and re-assigned to the division of HIV/AIDS prevention.  This group will be in charge of replicating findings of the Whittemore-Peterson Institute, rather than the group under the control of Dr. Reeves.  The move is highly significant: it appears that the CDC is now acknowledging the serious nature of XMRV.

The CDC will be part of an interagency working group on XMRV, led by Dr. Jerry Holmberg.  A three-part study will be initiated:

  1. The first part will consist of standardizing and validating laboratory methods and reagents for XMRV testing.  This stage will use samples provided by samples collected by Dr. Judy Mikovitz.  The intention is to create an FDA approved test.
  2. The second part will test a much larger sample than the initial study, trying to determine the prevalence of XMRV in the general population, and the blood supply.
  3. The third part will consist of how XMRV is transmitted, how it causes disease, and how it affects various subgroups of the population.
The forceful demotion of Dr. Reeves is a sign that the CDC is in damage control mode.  The HIV/AIDS prevention group in the CDC has many capable retrovirologists, who can provide years of expertise.  In my opinion, this turn of events should lead to balanced, common sense research.

Apricitabine May Be Effective Against XMRV

Apricitabine, an NRTI structurally related to lamivudine, may provide activity against XMRV Reverse transcriptase.  XMRV, like the drug resistant strain of HIV-1 contains the M184V substitution, explaining why it is succeptible to AZT and not 3TC (lamivudine).  The FDA has granted fast-track approval to the drug, meaning it should be available some time next year.  It appears to be extremely well tolerated, and was not associated with abnormal blood lipids, liver or kidney toxicity, or bone marrow suppression.

Sunday, December 6, 2009

Antiviral Study Shows Few Options

A new Study released by Sakuma et. Al this week, provides groundbreaking new information on therapies for XMRV.  The results are not good: 10 licensed HIV-1 anti-virals were tested - only 1 showed strong activity, and 1 showed weak activity.  Out of the RTI's, AZT, 3TC, Tenofovir, D4T, Efavirenz, and Nevirapine were tested - only AZT showed strong activity.  Previously I reported that 3TC and Emtricitabine showed activity against a closely related virus: 3TC has negligible activity against this beast, and Emtricitabine remains untested.  The mechanism for 3TC resistance is likely a Valine substitution at position 184, in place of a methionine.  Emtricitabine, Abacavir, Etravirine, and Zalcitabine remain untested.  Three protease inhibitors were tested: Ritonavir, Indinavir, and Saquinavir: Only Ritonavir demonstrated weak activity at high concentrations - something that was not unexpected.  One experimental integrase inhibitor was tested: the compound 118-D-24 which was ineffective, good news is that it is structurally distinct from Raltegravir, and 118-D-24 does not inhibit MLV integrase either.

A comparison of the sequences reveals some astonishing details: the XMRV Reverse-Transcriptase resistance mechanisms are astonishingly similar to HIV mutations: Valine at position 75 is substituted with Glutamine (d4t resistance), Lysine at position 103 substituted with Serine (Efavirenz resistance), A Valine at position 106 is substituted with Tyrosine (Nevirapine resistance), A Methionine at position 184 is substituted with Valine (3TC resistance).  A closer examination reveals another stunning detail - most other drugs targeting Reverse-transcriptase are not likely to work, as the mutations giving rise to their resistance in HIV are apparent in XMRV.  The only good news is that XMRV does not foster the critical 4 amino acid mutation giving rise the Multi-nucleoside analog resistance.  Raltegravir still holds promise, as XMRV integrase bears a close sequence homology to MLV integrase.

Certainly, it is not a good situation.  The toxicity of AZT leaves a lot to be desired - HIV have much more tolerable Reverse transcriptase inhibitors at their disposal.  The development of drugs effective against XMRV has to essentially start from scratch - determining X-ray structures of XMRV Reverse Transcriptase, Protease, and integrase, modeling candidate molecules, conducting clinical trials, and seeking FDA approval.  The sequence differences of XMRV reverse-transcriptase will provide incentive for HIV drug research - the differences are what also gives HIV-1 resistance to current therapies.  We are basically where we were in 1987 with HIV - with Didanose (ddl) being only the second HIV drug to follow 4 years later.

This study only reinforces the urgency of kicking XAND research into high gear - 18 years were lost due to what I call criminal negligence at the CDC, and I am not afraid to call it the worst medical fraud of all time - only the CDC and their research cronies would stand to benefit -- not the patients, not the drug companies, not HIV patients, and not the doctors.  If the findings of Defreitas had been properly handled, patients with neuroimmune disorders would have options, and HIV patients would have drugs to treat resistant HIV strains.

Sakuma, R., et al., Xenotropic murine leukemia virus-related virus is susceptible to AZT, Virology (2009), 

Two new Studies: Part I - Co-infections point to three strikes theory

A follow-up study was done by Dr. Kerr, demonstrating that ME/CFS symptoms are not caused by XMRV alone, but that co-infections have various additive symptoms - leading more credence to what I call a three strikes theory.  For ME/CFS to develop, you need the following three conditions to develop in a more/less orderly sequence:

  1. Infection with XMRV
  2. Co-infection with another etiological agent: various herpesviruses, certain bacteria
  3. Major immune challenge: Influenza, surgery, immunosupression
The basis of this research is that Dr. Kerr separated various CFS cohorts based on symptoms, and tested various consistent immunological disturbances based on certain pathogens present.  There was a definitive correlation between the severity of symptoms, and the type of infection present.  The four pathogens tested were: Eppstein-barr virus, enterovirus, parvovirus B19, and the bacterium coxiella burnetii.  In the test, a study was done looking at the differential expression of 88 genes.  There was also a regional difference in CFS subtype patterns: Birmingham, Bristol, Leicester, London, New York, and Dorset.

Here are my conclusions without getting into too much detail: even though EBV, Parvovirus B19, and Enterovirus have been fingered as triggering ME/CFS, it clearly tells me that they are not the cause.  ME/CFS has often been described as a heterogenous ailment of many possible causes: a theory that existed in AIDS patients before the discovery of HIV.  I believe that ME/CFS, FMS, and Gulf War syndrome bear a single unified cause, and that cause is XMRV.

XMRV is the first strike: without XMRV or closely related retroviruses you can't have ME/CFS.  If XMRV infects a normal individual, I am of the opinion that a healthy immune system can keep the virus in check for many, many years.  Over time, XMRV leads to an immune dysfunction syndrome, though not a severe life-threatening immune deficiency syndrome like AIDS.  XMRV is the mastermind.

The second stage, which I call the second strike, is what sets the stage for ME/CFS.  Throughout a lifetime, most of us will become infected with multiple persistent herpesviruses: EBV, HHV-6, Cytomegalovirus, Herpes Simplex... yet a healthy immune system can keep them in check.  At this stage, most XMRV infected individuals will probably remain asymptomatic.  The body now struggles to maintain the immune system at equilibrium, and it might take longer to recover from simple viruses like the common cold, and some patients might exhibit sub-clinical signs of ME/CFS.  The pathogen in this case plays the role of accomplice.

The third stage I will loosely call the third strike - the event that initiates ME/CFS I believe requires a period of prolonged immune activation, or inversely immunosuppression.  At this point, the immune system is ill-prepared to fight a war on another front.  In comes a pathogen that causes a vigorous and prolonged immune response such as a bacterial infection, or influenza, and now the immune response is mobilized towards it, retreating from the two previously acquired infections:  the viral burden initiates a chain reaction within immune cells.  XMRV viral load spikes, leading to the destruction of NK cells, and pathogens like EBV now seize the day, and begin replicating, and viruses like EBV can now cause immune downregulation, slowing the creation of new NK cells from progenitor stem cells, capable of arresting EBV.

Conclusion: ME/CFS, FMS, and Gulf war syndrome are caused by a common pathogen, which causes a common set of symptoms, and the heterogenous cluster of symptoms can be explained by co-infections with other pathogens.

Wednesday, December 2, 2009

Ampligen "Death Blow" Another Tragedy for CFS Sufferers

In a shocking move, the FDA yesterday refused to approved Hemispherx's drug Ampligen.  It represents a devastating blow for Hemispherx who have in vain attempted to garner approval for Ampligen for over 20 years.  In their response letter, the FDA essentially demands that Hemispherx begin their clinical trials from scratch.  They site initial clinical trials fail to convince the review panel of Ampligen's efficacy, and that new clinical trials be conducted testing different doses for at least six months, on at least 300 patients, compared to the previous study which enrolled just 230 patients.  The FDA also goes on to cite unresolved manufacturing problems.  Considering that the previous study took 6 years to complete, approval doesn't appear likely any time soon, and likely won't be approved in other jurisdictions, as other nations have followed the guidance of the FDA, with a handful of exceptions of drugs that have gained approval by the European Medicines Agency before FDA approval is granted.

For persons suffering from ME/CFS, FMS, and Gulf War Syndrome it shows that government agencies continue to recognize these conditions as a real illness.  And research dollars earmarked for CFS/ME research gets misappropriated by CDC bureaucrats as a slush fund, where not one meaningful study has come out of it.  And it appears recent developments have not shifted the groupthink mentality of the CDC - but it will come a time when they will find themselves standing pretty well alone if replication studies on XMRV are in line with those of the Whittemore-Peterson institute, which I have reason to believe will be.

I believe that psychologically Ampligen represents a huge setback, but in the end it will amount to no more than a bump in the road.  Tests on antiretrovirals are going ahead full steam in pharmaceutical labs as we speak, and I've dug up a couple of other compounds that have demonstrated activity against other retroviruses: Lamivudine and emtricitabine - both have a far greater safety profile than Zidovudine (AZT), posing a low risk of anemia, nephrotoxicity, hepatoxicity, and pancreatitis.  I'm not particularly fond of Non-nucleoside Reverse Transcriptase inhibitors, due to their unfavorable side effect profile - distressing rash in as much as 20% of patients, and severe liver damage seen with Nevirapine and Etravirine - making patient compliance and adherance to treatment an issue in itself.  I also don't favor a single drug regiment - I would like to see a combination pill of either Lamivudine or Emtricitabine with raltegravir.

Tuesday, December 1, 2009

Research Must be Pursued to The End.

One of my research interests currently is the isolation, characterization, and study of human retroviruses in disease.  The discovery of XMRV in CFS/ME represents just a small step.  Sufferers of neuroimmune diseases have been searching for answers for decades - without any explanation.  While it is still too early to tell if the results of the Whittemore Peterson institute will be replicated, it is the objective of most groups working in good faith towards this goal to do so.  If consistent results are reported on a worldwide basis, it's a huge victory.  Even if we see results which show a regional consistency - it still means something, and we have to keep looking further - hence a possible explanation for the difference in the findings of DeFreitas.

In such a case, I entertain the possibility that there maybe a handful of related retroviruses capable of inciting symptoms of ME/CFS, much like there are many viruses capable of producing cold like symptoms.  This is a research proposal that I have put forth to a group of academic institutions here in the UK, and I hope to have an answer soon.  At the least, I would not be surprised to identify multiple strains of XMRV on a regional basis throughout the world.  It would also be interesting to attempt to replicate the Defreitas study.

At this stage, I don't think it would be prudent to let a retroviral cause for neuroimmune disease slip us by once again.  I am for without a doubt certain that we have the cause of these disorders within sight - and we would be foolish not to think so.  We have large libraries of retroviral genomes to screen from, making the identification of closely related viruses readily possible - just like we have HIV-1 and HIV-2.  Over the years, we've accumulated evidence of a virus, and ME/CFS sufferers must be given answers, so all leads must be pursued to the end.

Friday, November 27, 2009

When Can Patients Expect Approved Therapies?

The availability of effective therapies for ME/CFS, FMS, and Gulf War Syndrome is still quite a ways off. Pharmaceutical companies have expressed a great interest in screening currently available HIV therapies, and compounds that did not pan out for treating HIV.  Likely it will be four years before the FDA approves any existing drug for treating XAND disorders - By next summer a number of drug candidates that work against XMRV will be selected for Phase II clinical trials (A Phase I trial is not necessary for a new indication), followed by a larger scale Phase III trial, which will likely not be completed well into 2012, with approval in 2013!  For new chemical entities, it will be even longer - at least that long for protease inhibitors (purifying the protein, doing X-ray crystallography studies, and finding small-molecule inhibitor candidates), then starting from scratch with phase I studies - what is going to turn out to be about a 10 year process, and likely the FDA won't grant accelerated review.

It's not to say that when results from ongoing studies begin to surface, that doctors won't begin the label of practicing current HIV drugs off-label to XAND patients.  However, such patients will have to shoulder the cost of treatment themselves, as insurers will be very reluctant to cover a drug which is not indicated for a particular disorder by the FDA.  High drug costs in the United States, which has been decried as criminal by AIDS activitists, will present a formidable barrier to most people.  In some countries with publicly funded health care systems, these drugs will be even harder to obtain: HIV patients have programs where drugs are given free of charge at clinics, and are not available in community pharmacies.  In some jurisdictions like British Columbia, which has a publicly funded drug plan, despite being approved for use by the federal government, the drug plan will do time-consuming studies which last on the order of 2 or more years, further delaying availability of treatment - so much for universal health care!

Norwegian Study Offers Clues

An experimental ME/CFS treatment in Norway involves some tantalizing clues: B cell depletion with Rituximab.  The study was initiated after a patient with CFS had unexpected, marked recovery of CFS symptoms following cytotoxic chemotherapy for Hodgkins's disease.  A following study was initiated recruiting patients, for B-Cell depletion therapy, all patients in the study demonstrated substantial improvement after the first infusion, followed by a relapse, improvement following the second infusion, and an even more marked  improvement after the third infusion.  This treatment will not likely gain a mainstay in ME/CFS treatment, as it poses a high degree of risk, costs over $10,000 a treatment, and would require infusions on an ongoing basis.

Nevertheless, it shows that B-Cells beyond a reasonable doubt play a major role in the pathogenesis of ME/CFS.  By depleting XMRV infected B cells, it can be seen that healthy B cells develop from progenitor stem cells, but soon succumb to infection - indicating that XMRV infects other classes of lymphocytes.  It leaves room to infer that antiretroviral therapy would have an even more profound and lasting effect: Most T-cells, with the exception of memory cells have an average lifespan of about 8 weeks. After a couple month course of antiretroviral therapy, it would not be unreasonable to see the vast majority of lymphocytes replaced by healthy cells

Fluge and Mella BMC Neurology 2009 9:28   doi:10.1186/1471-2377-9-28

The Modus Operandi: Part II

In my previous post, I gave my theory explaining the female predominance of ME/CFS and fibromyalgia, in this post I will explain my theory behind the neurological symptoms of ME/CFS, FM, and Autism.  My theory centers around the SYG1 membrane protein, which has been identified as a synaptic guidepost, directing neurons to connect to each other.  The SYG1 protein is in the immunoglobulin superfamily, with an extracellular domain, a single transmembrane segment, and an intracellular loop.  SYG1 binds to its receptor SYG2, which is also a member of the immunoglobulin superfamily.  Ironically, SYG1 is most heavily expressed during fetal development and early childhood, and its expression greatly diminishes thereafter.  In adulthood, it continues to be expressed in the limic region (which includes the hypothalamus), at neuromuscular junctions in skeletal muscle, and in arterial walls.  When it is activated, it initiates selective synapse elination through the SCF-Ubiquitin ligase complex - when it works properly, SYG1 binds to SKR, inhibiting formation of the SCF complex (Skp1-cullin-F-Box complex), protecting nearby synapses.

It is my opinion that SYG1 dysregulation is directly correlated to symptoms noted in all three conditions: ME/CFS, FMS, and Autism.  If you disrupt proper synapse formation in early childhood development, you almost certainly will end up with a developmental disability.  It leads me to theorize as some have that XMRV is passed from mother to child through saliva, body fluids, breast milk, and quite possibly placental transmission.  Likely the process of autism begins well before the first symptoms appear, and with XMRV screening could be reversed by early use of antiretrovirals, either by treating an infected mother, or the child.  There has been some mention by Dr. Mikovits that vaccines could create the immune insult setting off autism, however I believe the risk is far, far smaller than the immune insult from getting sick - as you are only exposed to an antigen at a point in time, as opposed to receiving a continuous onslaught of viral antigen while the immune system clears the virus.

Another interesting point is that SYG1 is primarily expressed in slow sodium fibers in the peripheral nervous system at neuromuscular junctions- nerve fibers responsible for transmission of pain signals - leading to an amplified pain response.  Substance P opens slow sodium channels, and closes potassium channels - and if you've got uncontrolled synapse formation, it may very well explain some of the observations made in FMS.

Vactruth strikes again - with even more defamatory information!

It is a site with slick graphics, designed to get you to believe their propaganda.  This week, Vactruth takes another stab at vaccines claiming that Chronic Fatigue is the result of a mouse virus contaminating vaccine reagents.  How can anybody invent this kind of psychotic diatribe "Well heres where the 'oops' comes in.  Every HIV-1 lab in the country uses TZM-bi cells for something.  All from the same stock from the NIH reagent bank.  Turns out this stock has been contaminated with another retrovirus - murine leukemia virus."
Whoever runs this site, thank you for your continued foolishness, dangerously misinforming the public - when you can't even spell here's properly, do you deserve to be believed?  They even make accusations against Glaxo Smith Kline for producing a deadly vaccine - three adverse reactions among 170,000 doses is not a lot - at least 250 people would have died from influenza complications had they not been vaccinated.  Far more people will get Guillian-Barre syndrome from contracting the flu, than getting the vaccine.

A site like Vactruth sickens me - and they hide their domain registration information and contact information - telling me a lot about their credibility.  If anybody knows who runs this site, please let me know, as I would like to have a few kind words with them about the defamatory libel they falsely and maliciously spread, in hopes you will not get vaccinated, and infect someone else.

Thursday, November 26, 2009

The Modus Operandi of XMRV: Pt1

In a 2 part series I will explain the mechanisms by which XMRV enters human cells, and possible consequences.  The cell surface receptors for XMRV have been identified as XPR1 and SYG1: XPR1 is G-protein coupled receptor suspected as a putative progesterone receptor.  The first part I will deal with deals with XPR1.

XPR1 is a membrane protein which acts as a signal transducer: it crosses the plasma membrane 7 times.  Recently, the structures of a handful of G-protein coupled receptors has been elucidated: Rhodopsin - a visual protein, Beta-adregenic receptor - adrenaline receptor and target for beta blockers, and the A2A adenosine receptor - the receptor our favorite wake up drug caffeine binds to.  XPR1 is found in a fairly diverse array of tissues: lymphocytes, hepatocytes, as well as cells in the brain, pancreas, kidney, prostate, and muscle.  This is a very important finding indeed.

It is of note that progesterone tends to shift the immune balance towards Th2, and that progesterone levels rise to as much as 10 to 15 times normal during the third trimester.  So, as a molecular biologist, it leaves me to theorize that if this virus can mimic progesterone, it can create a state that allows the immune system to ignore the virus, very much like it ignores a developing fetus - scary isn't it?  It is also worth noting that mutations in XPR1 bear a strong association with miscarriage, and that such women often bear masculine-like features.  Observations reveal that high rates of estrogen, or high rates of testosterone in the absence of progesterone tend to favor the growth of XMRV - progesterone inhibits the formation of DHT.  It seems to indicate that succeptibility to ME/CFS is strongly hormone driven, and why ME/CFS and FM are strongly female prevalent.

J. Battini, J.E. Rasko, D. Miller. (1998).  A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: Possible role in G protein-coupled signal transduction.  Proceedings of the National Academy of Sciences:

Scientific Consensus is Building Towards XMRV as Causal Agent of ME/CFS

I had the opportunity to speak with one of the researchers who attended the  Cleveland Clinic conference a short while back.  Since the landmark study appeared in Science last month, several groups have been in a race to replicate the findings of Dr. Judy Mikovits - preliminary results are beginning to come in, while other researchers are waiting for their virus samples to arrive.  There is now reasonable certainty that XMRV is the causal agent of CFS/ME, as opposed to probable grounds at the time of publication.  It is hoped that by the middle of next year XMRV will beyond a reasonable doubt be shown to be the causal agent of ME/CFS.

XMRV seems to follow Koch's postualtes, except for the first one: "The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy animals."  The third "The cultured microorganism should cause disease when introduced into a healthy organism", and fourth "The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specified causal agent." has yet to be shown.  However, the main criticism of Koch's postulates is that it does not account for asymptomatic infections.

It is worth noting that there was considerable attention paid to possible therapeutic agents for ME/CFS.  This is still very much of a gray area at this time - and it will be several months before it is known which existing HIV drugs will work against XMRV - only a couple Reverse Transcriptase inhibitors, and Raltegravir have shown early promising results.  This in itself has already led to a few doctors prescribing AZT off-label to ME/CFS patients outside of clinical trials, in addition to a handful of individuals purchasing the drug online from internet pharmacies - however AZT IS NOT a drug that should be taken without medical supervision under any circumstance.

Thursday, November 19, 2009

Raltegravir is likely effective against XMRV

Raltegravir (Trade name Isentress), is a drug that inhibits retroviral integrases.  In the article Beck et. al "Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir", the author states in Proceedings of The National Academy of Science that "the activity profile of raltegravir on the replication or murine leukemia virus is similar to that for HIV, and that the drug specifically affects autoimmune disease in mice, in which endogenous retroelements are suspected to play a role."  Both parts of this statement are highly significant.

The inhibition of Murine Leukemia Virus Integrase, which is almost identical to XMRV integrase, is not that surprising after all.  The catalytic sites of retroviral sequences have a series of conserved residues which are essential for activity, meaning that this enzyme is probably the best therapeutic target for XMRV.  Integrase inhibitors alone could work very well as monotherapy, and Dr. Mikovits stated that HAART is probably not necessary.  Because XMRV is a slow replicating virus, the chances of the virus becoming refractory to inhibitors of retroviral integrase are slim, as compared to HIV.  The drug raltegravir has a much, much better safety profile than NNRT's, which inhibit reverse transcriptase - which have side effects such as lipodystrophy, and the possibility of liver damage.  The downside is: Isentress is very expensive, costing about $1100 a month, something insurers definitely will frown upon - which may lead to some of them requiring a trial course of an NNRT before covering an integrase inhibitor.

The second part, where raltegravir induced lupus in genetically succeptible mice also could have a very profound effect in treating autoimmune diseases in the future.   What is significant is that Lupus favors one arm of the immune system, while Rheumatoid Arthritis, Psoriasis, Ankylosing Spondylitis, Crohn's disease favor the opposite arm.  This is significant, in that XMRV could induce the translation of endogenous retroelements - of which there are over 7,000 on the human genome -which human cells do not have the machinery to transform them into proteins (no human promoter can activate them), leading to the expression of foreign proteins on the surface of human cells, which makes the immune system recognize these cells as foreign.  It also lends credibility to the fact that Fibromyalgia is often co-morbid with disorders such as Rheumatoid Arthritis.  It also lends credence that Lupus is the polar opposite of RA, AS, Psoriasis - leading me to theorize that an antiretroviral could bring about a clinical remission in AS, RA, PsA patients - the same groups that currently benefit from anti-TNF therapy, but could exacerbate lupus.  So Lupus might be a true autoimmune disease, while on the opposite side a viral mediated quasi-autoimmune state exists.

**It is also noted that Echinacea extracts have been reported to produce lupus flares.

G.B. Beck-Engeser, D. Eilat, T. Harrer, H.-M. Jack, M. Wabl (2009). Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir Proceedings of the National Academy of Sciences : 10.1073/pnas.0908074106

Saturday, November 14, 2009

Will Ampligen Ever See The Light of Day?

For many ME/CFS patients, Ampligen offered a glimmer of hope for an effective treatment.  New developments which I've been monitoring however pour some cold water on the flame of hope that was burning for ME/CFS sufferers.  In an unexpected turn, the FDA has demanded additional data from Hemispherx Biopharma regarding safety data, and to perform additional clinical trials regarding its efficacy.  This did not bode well for the securities regulators, and shareholders, who filed suit claiming that it's CEO Bill Carter provided misleading information regarding Ampligen's regulatory status.

Something of this magnitude is by no means unheard of in the pharmaceutical company - Supergen's CEO Jon Rubinfeld was involved in a similar controversy with the drug Orathecin to treat pancreatic cancer.  It certainly will have a profound impact on the approval process for Ampligen.  Given the current situation, an approval for the drug should not be expected until  Q3 2010 at the very least.  Given the litany of lawsuits Hemispherx potentially faces, it could very well derail the Ampligen approval process, and bankrupt the company.  Hopefully, if this is the case, one of the pharmaceutical giants picks up Ampligen, and does the proper filings.

Monday, November 9, 2009

Chicoric Acid - A Natural Integrase Inhibitor.

Over the weekend, I pored over numerous scientific journals, and came across something particularly interesting when searching for inhibitors of XMRV Integrase - Chicoric Acid.  I found numerous studies done, showing that it inhibits not only HIV-1 integrase, but a broad spectrum of integrase enzymes.  This holds some potential as a low cost treatment, however its efficacy remains to be seen.  Chicoric Acid is one of the active principles in extracts of purple coneflower (echinacea).  For pharmaceutical companies, there is little interest in the compound, as it cannot be patented, however in the not-too-distant future we may see it appear on shelves of health food stores.

I for one, cannot guarantee its efficacy.  No pharmacokinetic studies have been done on it.  Normally, a lot of phytochemicals that show a lot of promise in vitro, have little to absolutely no effect in vivo.  This is because everything that is absorbed through the intestine is taken to the liver through the hepatic portal vein, where it undergoes first-pass metabolism, usually through the Cytochrome P450 enzyme system, followed by glucoronidation where it is eliminated through bile.  However, pharmaceutical chemists have devised clever ways to thwart the P450 system, by identifying key parts of the molecule that are vulnerable to attack, and replacing functional groups with Chlorine or Fluorine atoms, giving them a much longer half-life in the body.  Some of these analogs are already being studied as candidate compounds for HIV - for example it has been found that the carboxyl groups of caffeic acids are not necessary to inhibit integrase.'s Allegations of Vaccines Containing XMRV Laughable.

While doing some research, I came across a site called, which makes claims that vaccines that are developed to protect us are contaminated with retroviruses.  The author of this website is unknown, as all domain information has been registered privately - but the article is signed by this Dawn Crim.  I could see why she? would not want her information known - some of the information contained in her blog is just laughable!  The allegations sound like this person blames vaccines for allergies, ADHD, Anxiety, Depression, Lyme Disease, and her very own problems with fatigue.

First of all, any pharmaceutical company would do their due diligence, as they have their reputations to protect.  Second, the possibility of secondary retrovirus contamination nowadays is extremely remote - even with live attenuated vaccines, as they use multi-stage molecular sieves to screen out any contaminants, and most vaccines only contain parts of the virus - usually highly purified antigenic peptides.  Third, the claim that Squalene is carcinogenic is absolute hogwash!  Squalene is a natural oil-like substance that is found in copious amounts in shark liver oil, olives, wheat germ, rice bran, and amaranth seed - things that are found in abundance at your local health food store!  And on other ingredients in vaccines - would you drink water if someone told you it was toxic, Mrs. Crim?  The fact is everything is toxic in large enough amounts - just like the amount of mercury contained in a vaccine preparation is less than what is found in a tuna sandwich.  And no pharmaceutical company would conspire to deliberately mass poison a population through a vaccine - someone would blow the whistle, and company executives would face decades long prison terms, and the whistleblower would get millions for doing the right thing!

It sounds like the author of this article can add one more affliction to problems faced by herself and her family: Paranoid Schizophrenia. sounds more like a collaboration of patients in a state mental hospital working on a project to pass the time.  I hear it gets awfully boring and lonely in the Loonie Bin.

Google Robots Identifying My Blog As Spam?

I just couldn't believe it - Google's robots have flagged my blog as spam!  How ridiculous.  Some people can't see my new posts until some real humans read my blog and decide it is not spam.  I don't know how their robots work, but I am certainly not advertising any goods or services for sale on my blog, and I will only recommend products which have research behind them.

Saturday, November 7, 2009

Should You Get Tested For XMRV Now?

The XMRV test offered by VIP Diagnostics is basically a second generation test - the one where the Whittemore Peterson Institute announced that almost all ME/CFS patients were positive for XMRV, compared to the test at press time where only 67% tested positive.  The test is by no means perfect, and it is not yet clinically validated.  For persons who have severe disability, it's better than what they had before.  It's pretty impressive to go from 67% accuracy to 97% in such a short period of time - it is more accurate than current tests for lyme disease.

It takes a considerable amount of research to refine testing methods, some of which involves making DNA primers with higher stringency.  It also involves standardizing the test amoung several research institutions.  Blood banks will usually want a clinically validated test.  If you get tested today, there is still a small chance the test may not detect anything.  If you are willing to part with you money, it may provide some answers, however it might be better to wait until a clinically validated test is available.

Thursday, November 5, 2009

CFS - History of an Old Disease With Many Aliases

Chronic Fatigue-like illnesses have been described in medical literature for over a century-and-a-half.  The disease has went through many different name changes since then:

  • In 1751, Manningham described a syndrome of low-grade fever, weariness throughout the body, and pains.
  • 1760 - Dr. Snow described a new illness in West Otago, New Zealand as Tapanui flu.
  • 1816 - Fibromyalgia was first described by Dr. William Balfour as rheumatism.
  • In 1860, Dr. George Beard identified a syndrome with similarities to CFS that he called Neurasthenia.
  • In 1861, Florence Nightingale became ill with CFS symptoms.
  • 1884 - Sigmund Freud advocated cocaine use to alleviate chronic fatigue.
  • 1904 - William Weichardt described that CFS had an etiological agent.
  • In 1936, an outbreak occurred in a Wisconsin Convent.  The name Encephalitis was given to the condition.
  • 1937 - An outbreak occurred in two Swiss towns, that were described as abortive poliomyelitis..
  • In 1938 Dr. Alexander Gillam described an outbreak that occurred in 1934 at Los Angeles County hospital affecting all or most of its nurses and doctors resembling symptoms of today's description of Chronic Fatigue Syndrom.  Dr. Alexander Gillam gave the syndrome the name of atypical poliomyelitis.
  • 1915 - The AMA Journal referred to neurasthenia as an adrenal disorder.
  • 1939 - 73 Swiss soliders were given the diagnosis of abortive poliomyelitis.
  • 1948 - Outbreak at Akureyri Iceland.
  • In 1949-1951 over 800 people in Adelaide, Australia became ill with symptoms resembling the atypical poliomyelitis described by Dr. Alexander Gillam.
  • 1955 - An outbreak at the Royal Free Hospital in England, the first reference made to a neuroimmune condition with a proposed name of Royal Free Disease.
  • 1964 - A theory arose that CFS was chronic brucellosis.
  • In 1970, McEvedy and Beard proposed the name benign myalgic encephalomyelitis and mass hysteria.
  • 1982 - Lake Tahoe Outbreak - A large number of persons fell ill, with a mystery illness, and many never recovered.  Hippocrates Magazine proposed the name "Raggedy Ann Syndrome".
  • 1983 - The term Chronic Eppstein-Barr virus was used
  • 1986 - The Term Yuppie Flu was coined
  • 1988 - The term Chronic Fatigue Syndrome became widely accepted.
  • 1989 - 1990 - Edmonton Outbreak - Over 600 people reported symptoms resembling CFS, beginning in the fall of 1989.  Several cases were traced back to two student residences at the University of Alberta which began with a flu like illness at the beginning of the fall semester, where some blood abnormalities were noted.
  • 1990 - Researchers announced they found DNA sequences of a retrovirus in CFS patients, and presented their findings in Kyoto.
  • 1996 - CFS was described as a neuropsychiatric disorder.  
  • 2003 - A Canadian panel developed diagnostic criteria for CFS.
  • In 2006, the CDC recognized CFS as a serious illness
  • 2007 - Monterrey Outbreak - Several Catholic nuns fell ill with CFS in Monterrey, Mexico.  The CDC was enlisted to analyze the blood by Mexican health officials, but they declined.  Researchers at Guadalajara University noted abnormalities in the RNASE-L pathway.

Gulf War Syndrome - Evidence For An Insect Vector of XMRV?

Considering how similar Gulf War Syndrome is to CFS, it leads me to postulate that time will reveal they are the same illness - different identity.  How do I come up with this hypothesis - a large number of soldiers who served in Iraq during Desert Storm have been diagnosed and treated for Leishmaniasis - a sandfly borne disease.  The tagline in the movie Casablanca reads "Round Up The Usual Suspects" - Mosquitoes and Ticks are not endemic in the desert - so what is left - Sandflies!  Maybe even Leishmania is a vector for XMRV?

Battle fatigued soldiers are often immunocompromised from stress - and then a bite from an infected sandfly - you've got the perfect storm to set XMRV related disease in motion.  Out the window goes the hypothesis of spent uranium, exposure to toxins, and prophylactic use of Pyridostigmine Bromide as an antidote.  Most chemical warfare agents are Organophosphates, which also include common pesticides such as Diazinon, Malathion, Guthion - the effects of poisoning which do not resemble CFS symptoms at all, and Pyridostigmine Bromide is used as a treatment for Myastenia Gravis and to treat orthostatic hypertension - a complaint of CFS patients!

Is it time for CFS/FM/Gulf War Syndrome patients to wage a legal battle?

The cat is out of the bag: it can be said with reasonable certainty that XMRV is the single agent that sets the wheel in motion for the immune disturbances associated with XMRV.  According to a CDC insider which I have spoken to, the CDC long knew back in the late 1980's that a single viral agent would be capable of causing the perturberences seen in ME/CFS.  I've also heard from a patient in Toronto, Ontario who developed CFS 3 months after receiving a blood transfusion after a motor vehicle accident in 1994 - it's more than a co-incidence.  More information keeps surfacing each and every day about the CDC hanky-panky.

For patients, there is enough there to start looking at litigation against the CDC and other parties.  This would not come at a small price - going against the CDC would require hiring a law firm that specializes in high stakes litigation.  The CDC would not be the only defendant - the Social Security Administration and the American Red Cross likely share some liability.  How much is at stake - Billions.  Each CFS/ME/FM/Gulf War Syndrome patient costs $35,000 a year in lost productivity - that's $595 Billion!  It's also $595 Billion that the Social Security Administration does not have to pay out in disability costs, HMO's and PPO's don't have to pay in drug treatments, and that pension plans don't have to pay out!

Such a lawsuit is perhaps what is needed to "Stimulate" the CDC into recognizing that these disease have an infectious etiology, that they are not some idiopathic fire of unknown origin like they want us lemmings to believe.  They will be forced to admit that CFS/ME/FM/Gulf War Syndrome is another acquired immune deficiency syndrome, and that they've been covering up this silent pandemic for just too long.  Likely if a judgment was won, it would be an egg in the face of the CDC, but they would exhaust all appeals.  Likely other lawsuits would follow in other countries.  Perhaps even a movie by the name of Osler's Web, done with an A list director and Cast might embarrass the CDC enough to change  their ways.

Tuesday, November 3, 2009

Dr. William Reeves - Another Mark Whiteacre? Criminal Negligence Perhaps?

For those of you who don't know, Mark Whiteacre was a biochemist at Archer Daniels Midland, who is most famously remembered as one of the highest level corporate whistleblowers in the history of corporate America.  He got the inside scoop on a price fixing scandal on Lysine and other products, and got his bosses in trouble, while he himself had his own embezzlement scheme going on within the company.  A similar thing can be said about Dr. Reeves at the CDC - he blew the whistle on his bosses, and yet he continues to be hypocritical to the extreme by stating that the retroviral program at the CDC was taking the lead in an attempt to replicate the WPI XMRV results.

Reeves acted unethically by stating to the press that he did not expect the agency (CDC) to replicate the WPI findings of XMRV in ME/CFS patients.  He acted unethically in that he pre-judged someone else's findings, before doing any research of his own.  He put his credibility, and quite possibly his career on the line - and he will be watched very closely.  Falsifying data won't go over this time.

But why would the CDC engage in such sinister behavior?  Their mission is to protect the public from emerging infections, and in this case they've failed miserably.  The pharmaceutical companies rely on them to lay out their research roadmaps for the future - if they put out junk science, how is the pharmaceutical industry to develop new treatments?  And why would they want to intentionally try and deny scientific facts???

It's certainly not in the interest of the drug companies, CFS/ME/FM/Gulf War Syndrome patients.  It seems the CDC's motto is if it isn't a deadly disease, then feed them Thorazine, Zyprexa, and Amitriptylline, and keep them so sedated they can't think straight - something that's already difficult enough for these patients - now we'll turn them into living zombies!  For the drug companies this would only represent five or six dollars a day - so it wouldn't contribute much to their bottom lines - Amitryptilline and Thorazine are off patent and cheap.  But anti-retrovirals would be a potential goldmine for the pharmaceutical industry - rather than sell just to HIV patients, now they could quadruple their sales to CFS/ME/FM/Gulf War Syndrome patients.

So who would not want that?  The first that come to mind are HMO's PPO's, publicly funded health plans.  Having to pay $1000 or more for XMRV treatments for an indeterminate period of time is something they would not take sitting down.  The second that comes to mind is blood banks - now they've got to worry about tainted blood on an unprecedented scale - making HIV and Hep C look like child's play.  Then comes the issue of liablity and lawsuits - like in Canada after the Canadian Red Cross was found negligent.  If they can keep it as a neuropsychiatric illness, then they can keep putting off liability.  It's criminal negligence at it's finest - the CDC knew of a viral link for twenty years, and they failed to act on it, and thousands more people became ill!

Sunday, November 1, 2009

Significance of Co-morbidity of FM CFS/ME and Autoimmune Diseases

The co-morbidity of Fibromyalgia and several autoimmune diseases is well documented in medical literature.  It was accepted for a time that FM CFS/ME were autoimmune disease as well.  It leads me to theorize that many autoimmune diseases are not autoimmune diseases, but rather a consequence of an XMRV-mediated immunodeficiency syndrome.  The finding that the human genome contains many endogenous viral genes that cannot be expressed under normal physiological mechanisms, but can be turned on by certain viruses like EBV, and most likely XMRV makes this a distinct possibility.  So how could this happen?

Many viral proteins are membrane proteins - they embed in the lipid membrane of the virion.  Conceivably, our cells could start expressing these proteins at their surfaces, triggering an immune response.  Many retroviruses contain transcriptional transactivators which there is a strong possibility could accomplish this very event.  It is also conceivable that herpesviruses could work in concert with XMRV to amplify this effect.  An XMRV ravaged immune system in theory can't mount an effective enough response to keep EBV, HHV-6 levels below the "Noise floor".

Ultimately, the significance could be that one viral gene could mean Rheumatoid Artthritis, another could mean Ankylosing Spondylitis, and another could mean Multiple Sclerosis.  This hypothesis could also help explain why what we call autoimmune diseases follow a relapsing-remitting pattern. It could also help prove/disprove the concept of molecular mimicry.

Possible Explanation for Pain Processing Abnormality in Fibromyalgia

Over the years, studies have revealed that a pain processing abnormality as an explanation for the pain fibromyalgia patients experience.  Several observations have been made, noting elevated Substance P in cerebrospinal fluid, and increased Glutamate activity.  These observations are not a cause, but rather a symptom of a much bigger picture.  Some morphological studies have been done showing ragged red fibers in skeletal muscles, in addition to atrophy of type II fibers.  Surprisingly few studies of this nature have been done, considering that performing a muscle biopsy with a special needle is relatively simple, and does not require any incision.

The pain processing abnormalities in Fibromyalgia are not unique.  It has become clearly established that Interleukin-1 Beta is an inducer of Cyclooxygenase-2 mediated inflammatory pain hypersensitivity, which in turn up-regulates substance P and Glutamate transport.  Muscle pain in influenza bears a striking similarity to Fibromyalgia pain, although it resolves itself once the virus is cleared from the body.  In Fibromyalgia, likely the XMRV virus plays a pivotal role.

A CFS/ME/FM Timeline - We Knew About A Retrovirus All Along!

The linkage of CFS/ME to a retrovirus is noting new and suspicion began to grow that it was the case in Fibromyalgia as well.  The first documented findings that a retrovirus might be responsible for CFS/ME surfaced around 1985. The timeline of findings begins in 1985.

  • 1985 - Four out of 5 samples sent by Dr. Dan Peterson from the Lake Tahoe Outbreak tested positive for an HTLV-1 like virus.  Incredible disruptions were noted in flow cytometry of peripheral mononuclear cells producing grossly unbalanced CD4/CD8 ratios - showing CD8 cell depletion.  Scatter patterns were also noted in the flow cytometry which were previously only seen in HIV/AIDS infections.
  • 1986 - Dr. Robert Gallo - the co-discoverer of the HIV virus remarked after analyzing blood samples from the Lake Tahoe outbreak the presence of HHV-6A, in a manner consistent with an opportunistic infection in HIV patients.
  • 1988 - MRI brain scans showed abnormalities similar to HIV cases.
  • 1991 - Dr. Elaine DeFreitas published her findings that genetic material of a virus similar to HTLV-I had been found in a similar proportion of patients to the current study at the Whittemore-Peterson Institute, though no virus had yet been isolated.
  • 1992 - The CDC and Dr. James Gow would go on to state that the findings of Dr. Elaine DeFreitas could not be replicated.
  • 1994 - The CDC dismissed further findings of immune disturbances such as high RNASE-L activity and CD8 depletion.
  • 1995 - Research began to surface in CDC and NIH funded studies about pain processing abnormalities in Fibromyalgia - notably elevated substance P, and high Glutamate.  These studies would lead researchers to look for a neurological cause - leading to the theory that the "Volume control" is turned up too high in the brain's pain processing areas - something that certain cytokines are shown to do.
  • 1997 - Up-regulation of the RNASE-L pathway is demonstrated in another study.
  • 2001 - A study noted the shift in redox state in CFS patients just like in HIV.  The Redox shift leads to P450 decoupling from NADPH depletion, perhaps explaining the multiple drug and environmental sensitivities CFS/ME and Fibromyalgia patients experience.  Of note is the Cytochrome P450 enzymes are responsible for detoxifying drugs and environmental toxins.
  • 2007 - The XMRV virus is discovered for the first time in humans in Prostrate Cancer patients who have a rare genetic mutation.
  • 2009 - The Whittemore-Peterson publishes the discovery of XMRV as a likely cause of ME/CFS, showing the virus able to replicate and infect healthy blood cells.

Thursday, October 29, 2009

Autonomic Dysregulation Redux - Here we go Again!

This morning I noticed another article seemingly trying to dismiss the findings of the Whittemore Peterson institute by going back to the neuroendocrine model of CFS.  The so called "Paper" titled "How XMRV Retrovirus Findings May Fit With The Amygdala Hyperarousal Model for ME/CFS is written by Ahsok Gupta, a self-proclaimed expert on ME/CFS who states that he cured himself of ME/CFS after being struck by a viral-like illness after his second year of Economics at Cambridge University.  The irony of it is that Mr. Gupta is neither a medical doctor, molecular biologist, or biochemist.

This theory in itself does not seem to hold water - in studies where a drug was injected into the amygdala, the animals had better memory for retaining the task - quite the opposite of memory impairment seen in ME/CFS.  In his paper, he also blames overstimulation of the autonomic nervous system - which would be typically characterized by anxiety, hypertension, and digestive disturbances (Something that occurs with use of cocaine, crystal meth, or even too much caffeine) - quite the opposite of ME/CFS!  He also goes on to theorize that the XMRV virus is simply a passive opportunistic infection which establishes itself due to general suppression and dysfunction of the immune system from autonomic dysregulation and amygdala hyperarousal (Would manifest itself as mania and hypersexuality).  Once again, this theory brings ME/CFS back to the forefront as a fire of unknown origin.

I stand firm that XMRV directly causes the symptoms of ME/CFS, FM, and Gulf War Syndrome - much like HIV causes AIDS.  Gupta quotes "There are two broad aspects to the immune system, Th1 and Th2.  Th1 involves Natural Killed (NK) cells whose job it is to identify and destroy viruses.  The Th2 side of the immune system involves amongst other things antibodies which respond to threats.  There is evidence in the litterature that patients with ME/CFS are Th2 biased..."  Enough said - some of this is partially true, but it does not meet the definition of a cause.  Years of AIDS research has already given us a heads up on what could be happening in XMRV infections.  HIV infects by latching on to the CD4 molecule for entry, much like I postulate that XMRV uses the CD8 Molecule found on NK cells, explaining why NK function is disrupted - saying that if the Th1 arm of the immune system is attacked, the Th2 system is going to be predominant.

To dissect this further, Gupta goes on to state that "The XMRV virus may simply represent one of many viral and bacterial infections present in the blood of ME/CFS patients, and that many of these previous infections (including EBV) have been previously prematurely suspected as the root cause of ME/CFS."  My take on this is look no further than HIV - as the disease progresses to AIDS, titers of CMV, EBV etc. rise dramatically - to the point where some AIDS patients have to take Valcyte to prevent sight-threatening CMV infections.  You also see that RNASE-L is elevated, and the uber-powerful cleaved version is present because RNASE-L functions to keep viral pathogens at bay until NK cells are summoned - unfortunately no one is there to answer the call

I also believe that the autonomic disruption in ME/CFS, FM, and Gulf War Syndrome is a direct result of infection with XMRV.  We've seen this in HIV - AIDS Dementia Complex.  The action of certain cytokines on the nervous system is also of note - anyone who has had the flu can tell you just how tired they are, and feel "spacey" - persons receiving interferon report the same.

I will finish by saying that ME/CFS, Fibromyalgia, and Gulf War Syndrome patients have been bombarded for years with faith healers, alternative/complimentary medicine theories, and psychiatric explanations for their symptoms.  No currently approved treatment has produced any satisfactory improvement in any of this group of patients, although some improvement has been noted with anti-virals targeting herpesviruses such as HHV-6, EBV, CMV lending to the credence that EBV exacerbates symptoms of an XMRV infection.  It will be interesting to see early results of AZT trials, and hopefully more HIV drugs will show efficacy - hopefully the integrase inhibitor Isentress will show efficacy against XMRV due to its lack of delitirious side effects like lipodystrophy, hypercholesterolemia and hyperglycemia found in protease inhibitors and some RTI's.

Wednesday, October 28, 2009

The "Normal" 4% Living XMRV Postive

In the findings by the Whittemore-Peterson Institute, roughly just under 4% of the normal control population tested positive for XMRV.  It would be really interesting to take these so called "normal" subjects in another study, and further examine them.  I hypothesize that a segment of these people are asymptomatic, much like many HIV positive individuals live asymptomatically for many years before developing AIDS, and I would not be surprised to see an alarming number of this 4% of the "Normal" controls demonstrating some mild symptoms that would not be enough to meet the diagnostic criteria for XMRV Neuroimmune disease.  Some of the mild symptoms that I postulate would be found include, but are not limited to:

  • Autistic Spectrum Disorders (Asperger's syndrome, Pervasive Development Disorder)
  • Mild fatigue previously attributed to depression
  • Intolerance to cold
  • Intolerance to physical activity
  • Lack of libido
  • Mild immune deficiency (ie: Picking up every cold or flu going around)
A thorough study of the "Normal" XMRV positive individuals should be performed to broaden our understanding of the disease process.  Eventually, we might be able to answer the question that if XMRV is the primary insult to the immune system setting the wheels in motion for XAND disorders, what factors contribute to developing full-blown disease?  The answer might be as simple as having too many simple viral infections like the cold or flu over a short period of time - meaning that the immune system of XMRV positive individuals functions in a near-normal manner, until it is brought to a threshold where there are not enough healthy Natural Killer cells to keep XMRV in check, allowing the total viral load in the body to slowly build with other persistent viruses like EBV, HHV-6 - contributing to symptoms.  This probably explains why Valcyte has shown a limited response in some individuals with Chronic Fatigue, though it has not produced dramatic improvements.  It shows that there is some truth in the statement made by Dr. Marshall that XMRV is not responsible for all the symptoms of Chronic Fatigue, but I still firmly hold my belief that XMRV is the cause, and that other Co-infections increase the cytokine burden, but there are not enough healthy NK cells to respond to the alarm, leaving a smouldering fire, which is Chronic Fatigue or Fibromyalgia.  It leads me to believe that after being treated with an antiretroviral for a fixed length, the immune system could be once again competent to keep XMRV in check, and that simply monitoring viral load afterwards and resuming an antiviral if the viral load exceeds a certain threshold could make a big difference.

Sunday, October 25, 2009

Chronic Fatigue Advisory Committee Meeting

This week, the Chronic Fatigue Advisory Committee will meet, and listen to the findings of Dr. Daniel Peterson.  The advisory committee has representation from the FDA, CDC, NIH, HRSA, and Social Security Administration.  The event is essentially a make-or-break event - will the evidence be strong enough to persuade the various agencies to start paying more attention to Chronic Fatigue Syndrome, that is the question that remains to be asked.

Over the years, the CDC has finally begun to realize that this disorder is reaching alarming proportions.  However, the system failed patients - the CDC essentially works hand in hand with the NIH - if the CDC doesn't believe something, the NIH does not grant research funds to institutions into that particular field of interest.  Precisely, this is what happened with the findings of Defreitas et. al years back - no research dollars flowed to anyone wanting to search for a virus responsible for CFIDS.  Without this, no drug companies are willing to invest in something that is unproven.

The current findings basically confirm earlier findings from research done be Dr. Elaine Defreitas.  This time, the difference is that Dr. DeFreitas did not actually isolate and characterize the virus, but found clues to its existence - this time we have a virus.  Hopefully, millions of dollars in research grants will flow to studying XMRV, rather than studying various neurological phenomena.

Accessibility to New Treatments

Even if treatments were to be approved by the FDA, or the medicines and health products regulatory agency, likely the such drugs would be well out of reach for most people. Since most people with Chronic Fatigue, or Fibromyalgia are already significantly disabled, their ability to earn income is severely curtailed. HMO's, PPO's, primary care trusts (UK), and provincial health care plans (Canada) are unlikely to foot the bill for some time. For pharmaceutical companies, it could provide a considerable disincentive for developing new medicine - likely drugs from the current HIV portfolio will be screened for efficacy initially. Currently, these drugs vary in price from $263 a month, to $2314.50 a month. If approved, Ampligen is expected to cost around $1300 to $1500 a month.

An approach that has been seen by many providers has been to restrict access to medications using certain criteria. In the case of XAND (XMRV associated Neuro Immune Disease) such as Fibromyalgia, Chronic Fatigue Syndrome, the approach insurers may likely take would be to demonstrate a certain level of disability, and have failed other drugs beforehand. A primary care trust for example might require a certain disability score and fail to respond to a course of Lyrica and Ritalin. For insurers, the cost of treatment remains to be determined, and the following questions need to be addressed over time:

  • Is the new drug more effective than the old one?
  • What benefit does the drug have in terms of quality adjusted life years score?
  • Will a lifelong course of medication be required as in HIV?
  • Will other antivirals be required to treat co-infections, such as cytomegalovirus, EBV, HHV-6?

Sunday, October 18, 2009

Current and Future Approaches to Treatment

Treatment options for Fibromyalgia and CFIDS sufferers are currently few and far between. There are no FDA approved medications specifically indicated for treating Chronic Fatigue Syndrome, and Lyrica is the only drug approved for Fibromyalgia thus far, with few options coming down the pipeline. Drugs currently prescribed for the condition include:
  • Amitryptilline - Based on the theory that Chronic fatigue is caused by a neurotransmitter imbalance, Amitryptilline is frequently part of the drug regiment offered to Chronic Fatigue patients, whereby it is postulated that it helps regulate sleep, as it is thought that in CFS or FM, very little time is spent in stage 4 sleep. Controlled blind studies show that it is not very effective, providing only a slight benefit over placebo.
  • Ritalin (methylphenidate), Desoxyn (methamphetamine), Dexedrine (dextroamphetamine), Provigil (Modafinil) - Drugs in this category act as CNS stimulants. The first three have the effect of raising blood pressure, and are indicated in treating postural hypotension, and promote wakefulness in CFIDS individuals. Modafinil does not address postural hypotension, therefore it is of limited use. For these patients, stimulants make it possible to perform daily tasks, however they do not seem to have an appreciable effect on cognitive impairment.
  • Lyrica (Pregabalin) and Gabapentin - Gabapentin is a drug used to treat epilepsy, which gained off-label use to treat neuropathic pain, Lyrica being the active metabolite of Gabapentin. Lyrica was the first drug approved for Fibromyalgia, until the approval of the antidepressant Cymbalta (duloxetine). Response to Lyrica has not resulted in statistically significant improvement in quality of life in FM patients. The cost of the drug is high, and many insurers will not cover its cost, and the opioid analgesics like Dilaudid (hydromorphone), and fentanyl seem to confer the greatest benefits. Lyrica is known to cause marked weight gain, and can be very sedating (CNS depressant).
Current experimental treatments have shifted towards anti-viral compounds. Anti-virals currently being prescribed off-label include Valtrex (Valacyclovir), Valcyte (Valgancavir), and Acyclovir - all targeted towards herpesviruses. Some patients note significant improvement, lending to the theory that having high viral titers of herpesviruses adds to the disease burden of XMRV. Equally significant results have been obtained with Isoprinosine, which is available on both sides of the border at a reasonable cost. Valcyte has the distinction of being extraordinarily expensive - >$1500 a month, and it is not without severe side effects. Ampligen is a drug if approved that would be the first drug approved specifically for treating Chronic Fatigue Syndrome - it is expected to cost ~$1500 a month for treatment.

Future treatment will likely involve treatment with anti-retrovirals. As the link between Chronic Fatigue Syndrome and XMRV becomes more clearly established, likely more practitioners will be willing to try current anti-retrovirals on Chronic Fatigue and Fibromyalgia patients. Three potential viral targets might include reverse-transcriptase, XMRV polymerase, and intergrase. Initially, AZT has shown activity in vitro against XMRV, however the toxicity of AZT limits its use - it's fine for someone who would otherwise die of AIDS, but it leads to an ethical dilemma when prescribing it in a situation where the side effects may be worse than the disease. Most NRT's and NNRT's are fraught with side effects such as lipodystrophy - which can be quite disfiguring. Protease inhibitors are slightly more benign, although some are known to cause dramatic increase in blood lipids. Integrase inhibitors are prehaps the most benign, being well tolerated, producing few metabolic abnormalities. Protease inhibitors may not work against XMRV, as the catalytic site may be sufficiently different than the HIV protease - being the case, it would require determining the atomic structure of the XMRV protease, in order to develop effective drugs. As the function of other proteins of XMRV become unravelled, other drug targets could conceivably be developed - one of these being the androgen responsive element or ard.

How is XMRV acquired?

Without doing further studies, it is difficult to establish exactly how XMRV is acquired. Being a retrovirus, it is as sure as the setting sun that tainted blood products, and injection drug use being some of them. A study by Umberto Tirelli in Archives of Internal medicine "Clinical and Immunologic Study of 205 patients With Chronic Fatigue Syndrome: A Case Series From Italy", seems to indicate some interpersonal mode of transmission between household members and casual contacts, appear to have been infected with a virus related to HTLV-II.

The initial onset of the disease with flu like symptoms seem to suggest an acute phase, where perhaps the virus is spread by droplets much like influenza. A certain amount of credence must be given to such a scenario, given that a number of young catholic nuns at a convent in Monterrey, Mexico were afflicted with the disease in 2003-2006, complaining of general malaise, and body aches which upon physical examination revealed little. This brings into question that maybe XMRV is spread through saliva as well, meaning that sharing utensils could transmit the disease.

The possibility of an insect vector cannot be ignored. Mice being a reservoir of XMRV, leads to the distinct possibility that blood sucking insects such as mosquitoes, sandflies, horse flies, and ticks could transmit the disease to humans.

The CDC Failed CFS Sufferers in 1991 And Continues to do so Today.

In a landmark paper written by DeFreitas et. al, "Retroviral sequences related to human T-lymphotrophic virus type II in patients with chronic immune dysfunction syndrome", the authors stated that an association had been made by a yet unidentified retrovirus, and Chronic Fatigue Syndrome. It was during my tenure with the CDC in Atlanta that the CDC quickly jumped to the occasion and refuted the findings in the paper, pouring cold water on the retrovirus link. For the next 18 years, many theories surfaced about Chronic Fatigue Syndrome, with no answers - the phrases "hypothalmic dysregulation", "Neuropsychiatric disorder", "Neurally mediated hypotension" being all too common.

Meanwhile, a scandal was unfolding with our neighbors to the north where just two years ago the Canadian Government announced $150 million in compensation for those infected with HIV through blood products, and around the time the paper written by DeFreitas, details began to emerge about persons contacting Hepatitis C from tainted blood. A similar blood scandal like those of our Canadian neighbors was the last thing the CDC wanted - when the word "Retrovirus" was uttered, fear struck among the top brass of the CDC - notably Dr. Brian Mahy, prompting director William Roper to convene an emergency meeting with Louis Sullivan, then Secretary of US Department of Health and Human Services, and the director of the National Institutes of Health.

The result was simply scandalous.  Dr. William Reeves became installed as the head of the CFS/ME research program where under the command of his superiors namely Dr. Brian Mahy, many sinister things began to happen to the CFS/ME research program.  The experiment done by Dr. DeFreitas had essentially been rigged, and the CDC sent Dr. James Gow a standardized primer solution containing a fixed concentration of magnesium - so his lab would report a similar result.  During my tenure at the CDC during my research fellowship, we were told we would not be flying to Philadelphia because there was a lack of funds to buy airplane tickets.  It later turns out that $12.9 million dollars earmarked for CFS/ME research had been misappropriated and funneled to other projects, $8.8 Million was granted to pharmaceutical companies who sat on the money and did nothing with it, and $4.1 million dollars unaccounted for.  The Inspector General of the Department of Health and Human Services confirmed that $13 million in CFS/ME research money was either mismanaged and/or embezzled.  Following this report, the General Accounting Office noted research had declined on CFS at the NIH since 1996, there was a lack of communication between the CDC, and NIH about CFS research, and the leadership of the DHHS was ineffective in leading the CFS coordinating committee.

What ensued would have a profound effect on Chronic Fatigue Syndrome research for the next 15 years. Research funds for the disorder literally dried up overnight, and research came to a standstill. Shortly after the paper authored by Defreitas et. al. came out, the CDC was quick to refute their findings, and no further studies were made to isolate a virus. Basically, after the CDC has published their findings and used Dr. Gow to manipulate the results to appear as inconclusive, the NIH would no longer provide the research team of DeFreitas et. Al with further research funding on the matter or anyone else for that matter - it was case closed - NO RETROVIRUS! Now according to the CDC, CFS was a symptom of unknown etiology that had both psychiatric and neurological influences, and the NIH granted funding to find a neurological basis for the disease, which for the next decade would offer us some insights, but still no answers.

The fact is that we had our man 18 years ago, but we were too quick to rule him out as a suspect, and he's been out on the lam for the last 17 years. Rather than face the music, the CDC chose to stick their heads in the sand, and have it all come back in their at a later time. It begs the question of just how many people have been infected with XMRV through blood products , when we could have been testing our blood supply for at least the last 16 years? Lest not forget that antiviral drugs targetting XMRV would likely be available now had research been pursued.

Plausible disease models

Until now, no good disease models existed to explain to etiology of Chronic Fatigue Syndrome and related disorders. In the 1980's, we called it the yuppie flu, in the 1990's we called it a neuropsychiatric disorder of unknown etiology, then we called Fibromyalgia a pain processing abnormality with hypothalmic disturbances, and for a period of time both conditions became a wastebasket diagnosis. There were no tests available to mainstream medicine that could precisely detect disease markers, although over time various researchers have uncovered slight abnormalities in patient's immune systems.

A good disease model can be explained by the disease pyramid - succeptible host, pathogen, environment, time. My disease model begins with the succeptible host - Man, pathogen - XMRV, environment - stress, and then time. Succeptible host needs some explanation, as does environment, with pathogen and time being constants. I will begin with the host:

Basically, not all human beings are created equal, but being simplistic the prevalence of Fibromyalgia is heavily biased towards women, and chronic fatigue somewhat less. Based on the genome sequence of XMRV, it appears that one gene functions as an androgen responsive element - does it bind androgens and act as a repressor? Further studies will be needed to answer that question, although it provides a plausible explanation. It could also mean that men who have low testosterone levels are more prone to developing disease. Once again, a promising lead that needs to be studied.

Now my model will explain why some people may live symptom free for years. In a state of homeostasis, the immune system efficiently keeps the virus in check.
  • Pregnancy - during pregnancy the balance of the immune system shifts towards Th2, likely from the influence of progesterone, this means that the body's defenses towards viruses are diminished.
  • Stress - Cortisol is a hormone produced by the adrenal glands in response to stress - small amounts are needed to keep the immune system in balance. Larger amounts will generally tend to suppress the Th1 response more than the Th2 response, thus tipping the balance. Emotional stress, sleep deprivation, caffeine, trauma and over-exertion all increase cortisol.
  • Infection - certain infections will favor a Th2 response - extracellular parasites (bacteria, protozoa, etc), and in the process will distract a Th1 response.
But when the balance tips, the XMRV in Nk cells begins to replicate, and infect other Nk cells, and the immune system becomes weakened as Nk cells become depleted, however does not result in a complete immune collapse, as other lymphocytes can partially fill the role of Nk cells, although with much less efficiency. Nk cells are important in recognizing cells infected with herpesviruses (Eppstein-Barr, Cytomegalovirus, HHV-6, Herpes Zoster, and Herpes Simplex 1 & 2), and with diminished numbers, the various viruses that have been identified in Chronic Fatigue and FM sufferers begin to flourish. A futile cycle ensues, where interferon pathways become activated, where RNase-L destroys cellular RNA in an effort to stop viral replication. Likely the fatigue results from chronic interferon activation, in addition to possibly the presence of a viral protein in the blood which acts as an endocrine disruptor. Confidently, I can say that based on this disease model, XMRV is the puppet master of Chronic fatigue. If you can suppress XMRV, Nk cell function will return, and the immune response will now keep herpesviruses in check. Once the immune system becomes competent, or reconstituted you might say, XMRV will be kept in check, until the host defenses are compromised.

Saturday, October 17, 2009

The relationship between HIV and AIDS, XMRV and CFS or FM

The million dollar question is - does XMRV cause Fibromyalgia, or Chronic Fatigue syndrome. Here's the spin - just like HIV patients, I theorize that many persons infected with XMRV can live symptom free for years. Many people report an initial onset of illness which causes symptoms reminiscent of a general viral infection like the flu - probably where the virus grows to very high levels, and then drops after the immune system begins to attack the virus, but later the virus damages the immune system where a competent immune response cannot be attained. If you look at the paper published by the Whitemore Peterson Institute in the Journal Science on Oct. 8th, 2009 - the initial findings are no surprise. Almost all CFIDS patients produced antibodies to XMRV - translation: XMRV beyond a reasonable doubt causes Chronic Fatigue Syndrome. XMRV could be detected in two-thirds of chronic fatigue sufferers - translation: Until a more sensitive assay is developed, the one-third where no virus was detected probably means that viral load was below the limit of detection. XMRV was found in 3.8% of healthy controls - translation: This probably means two things - a small percentage of false positives, and like having HIV doesn't mean you have AIDS, having XMRV does not mean you have chronic fatigue, although at some point in the future you will develop the disease.

A Primer on XMRV

XMRV is a retrovirus - a virus that uses its RNA to copy its genetic material into host DNA. The best known retrovirus is HIV (Human Immunodeficiency virus) - the virus that causes AIDS. XMRV is only the third such retrovirus discovered to infect humans, after the discovery of HTLV. Like HIV, XMRV has 3 genes in common - gag, pol, and env. The gag gene encodes the capsid and matrix proteins, the pol gene encodes a single protein which is cleaved into three separate proteins by the viral protease - reverse transcriptase, viral protease, and integrase, and the env gene encodes the envelope glycoproteins. The XMRV also contains an androgen response element gene, which I will discuss a theoretical role in a future post. The XMRV genome is somewhat smaller than the HIV genome - 8161 base pairs as opposed to ~9500 base pairs in the HIV genome. Based on initial findings, it appears that XMRV infects the immune system in ways that are all too familiar in HIV. The envelope glycoproteins likely bind to some yet unknown immune system protein like HIV binds to the CD4 receptor, and co-receptor, possibly CD8, CD 16 or CD 56 on the surface of NK cells.

A New Era of Hope

This week's publication in the journal Science literally blew me away! Not in the sense that it's just another virus, but in the sense that the findings about XMRV show an eerie resemblance to those made by Dr. Robert Gallo, and Luc Montaignier in 1984. Though the results are still very preliminary, there seems to be an arrow pointing at Chronic Fatigue syndrome, and an even bigger arrow pointing back at XMRV. I think this time we've got our fugitive, and in time he will be found responsible for more than Chronic Fatigue Syndrome and Fibromyalgia. He's already a suspect in Autism.