Retroviruses and Chronic Fatigue Syndrome

One of the themes of this blog is that chronic infections, exacerbated by bad diets and malnutrition, are at the root of nearly all health problems.

With the invention of new tools for microbiology over the last 20 years, scientists are for the first time able to study chronic parasitic infections, albeit with difficulty. I mentioned a few weeks ago that this should be the dawn of a “golden era of antimicrobial medicine.” And maybe it is: careful studies are now linking specific pathogens to chronic diseases and discovering the mechanisms by which they cause disease.

A good example of emerging science is the progress made since 2002 in understanding a retrovirus family that is now firmly linked to cancer and chronic fatigue syndrome and may soon be linked to other diseases.

Beginning of the Story:  Human Anti-Viral Immunity and Chronic Fatigue Syndrome

Our story begins back in the 1970s with studies of the role of interferons in defending human cells against viruses. Interferons are a key part of the immune defense against intracellular pathogens – the ones that cause most human chronic diseases.

Following the effects of interferons, researchers discovered an enzyme known as ribonuclease L (RNase L). RNase L is upregulated by interferons and its function is to degrade RNA, both viral and human, to stop viral replication. [1]

Aside: High levels of RNase L destroy so much human RNA that the cell dies. This is probably adaptive for the host, since cell apoptosis also kills many pathogens within. However, it shortens lifespan. RNase L knockout mice have extended lifespans. [1]

In 1997, RNase L was found to be strongly upregulated in chronic fatigue syndrome patients. [2] This showed that chronic fatigue patients usually have viral infections. Whether the viruses were causing chronic fatigue, or just “hitchhiking” with a disease that suppressed the immune system (perhaps via a bacterial infection?), remained an open question.

A Link Between RNase L and Prostate Cancer

By the early 2000s it was established that a common (allele frequency 35%) gene mutation, the “R462Q” mutation which substitutes a glutamine for an arginine in the “hereditary prostate cancer 1” locus, raised the risk of prostate cancer. A man with two copies of this mutation has twice the risk of prostate cancer; one copy raises the risk by 50%. About 13% of prostate cancer cases were attributable to this mutation. [1, 3, 4]

It was important, therefore, to determine which protein this locus coded for. A breakthrough finding, made in 2002, was that the “hereditary prostate cancer 1” locus was the gene for RNase L. [5]

It was soon shown that the R462Q mutation decreased the effectiveness of RNase L at cleaving viral RNA. This placed prostate cancer in a new light: it implied that an unknown virus against which RNase L defends was a probable cause of prostate cancer. When RNase L function was impaired by the R462Q mutation, the infection became more virulent, and prostate cancer rates were higher. [1]

The search for this unknown virus was on.

The discovery of “xenotropic murine leukemia virus-related virus” (XMRV)

The strategy was basically to take prostate tumors and search for viral RNA, looking for viruses that were most common in patients who had the double R462Q mutation.

In 2006 one of these searches yielded fruit.  A new gamma retrovirus was found in 8 of 20 prostate cancer patients with double R462Q mutations, but only 1 of 66 patients without the double mutation. [6]

This gamma retrovirus shared a lot of RNA with a family known as the xenotropic murine leukemia viruses (MuLVs). It was dubbed “xenotropic murine leukemia virus-related virus” (XMRV). Despite the sound, it is not a murine (mouse) leukemia virus; it merely shares a lot of nucleic acids with those viruses.

Back to chronic fatigue syndrome

In 2009 a paper was published in Science reporting that XMRV was found in peripheral blood cells of 67% of chronic fatigue patients but only 3.7% of healthy controls. [7] This study was done by a group at the Whittemore Peterson Institute in Reno, Nevada.

Aside:  The Whittemore Peterson Institute has a nice Q&A about this virus and its role in chronic fatigue syndrome here.

A number of researchers tried and failed to reproduce these results. For instance, a group from the Centers for Disease Control failed to detect XMRV proteins in 51 chronic fatigue and 53 healthy patients. [8]

Perhaps proteins are just not the right molecules for detecting this virus. A new paper has just appeared that links XMRV more strongly than ever to chronic fatigue. It looked at DNA for viral genes inserted into the human genome and found XMRV sequences in 86.5% of chronic fatigue patients but only 6.8% of controls. [9] This paper was held back from publication since June because of its conflict with the CDC paper (see “Why I Delayed XMRV Paper”), but has now been released.

These percentages are impressive and, if they hold up, would seem to make it unlikely that XMRV is merely a “passenger” virus hitchhiking on a suppressed immune system. It may be causal for chronic fatigue.

Will anti-retroviral therapies be effective?

Clinical trials are extremely expensive and the drug companies seem to be waiting for XMRV to be proven as the cause of chronic fatigue before undertaking trials. From the Wall Street Journal:

Norbert Bischofberger, chief scientific officer at Gilead Sciences Inc., the leading maker of HIV drugs, said the company might consider a small pilot trial but would like to see stronger evidence that the viruses cause CFS before launching a large trial. Still, “I’m very open, and this would be a great opportunity,” he said.

A spokesman for Merck & Co., another major manufacturer of HIV drugs, said: “A clinical trial program would be possible to develop only after further substantial evidence of an association with CFS.” [10]

But some aren’t waiting for trials. Anti-retroviral drugs developed for AIDS are being prescribed off-label:

Jamie Deckoff-Jones, 56 years old, a doctor and CFS patient in New Mexico, has been blogging about her experiences and those of her 20-year-old daughter. Both tested positive for XMRV and are taking a combination of three anti-retrovirals.

Dr. Deckoff-Jones said a year ago she could only get up for short periods during the day. After five months on the drugs, she flew last week to Reno for an XMRV conference. Her daughter was able to go to a party and is enrolling in community college. “This is all very new, and there is no way to know if improvement will continue,” Dr. Deckoff-Jones wrote in an email, “but we appear to be on an uphill course.” [10]

Chronic fatigue patients are celebrating the progress:

Many [CFS patients] were ecstatic at news that the second study was being published.

“We’re really hoping this will blow the lid off,” said Mary Schweitzer, a historian who has written and spoken about having the illness. “Patients are hopeful that now the disease itself might be treated seriously, that they’ll be treated seriously, and that there might be some solution.” [11]

It’s sad that for decades many haven’t taken chronic diseases seriously. The absence of a known cause reflected only the lack, until recently, of microbiological tools capable of detecting and characterizing intracellular pathogens.

Had doctors taken these diseases seriously, the accumulating evidence that these were chronic infectious diseases caused by intracellular parasites might have encouraged them to look for the sort of dietary and nutritional therapies for chronic disease that we advocate on this blog. Though diet and nutrition by themselves will probably not cure these diseases, they can greatly slow disease progression and improve the odds of a cure.

A new name for XMRV: Human Gamma Retrovirus

The Whittemore Peterson Institute recently hosted the first official scientific symposium on XMRV. Dr. Joseph J. Burrascano reported from the symposium:

We formed a working group to be in constant touch and we plan to meet regularly because advances are coming so rapidly.

Big news that everyone should know and adopt is that we have proposed a name change for the virus.

This virus is a human, not mouse virus, and it is the first and so far only gamma-retrovirus known to infect people. Also, it is clearly not an “endogenous” retrovirus (one that is present in all genomes due to ancient infection).

Because of all of this, and because of the desire to begin on the right track, the new name of the virus is HGRV- Human Gamma Retro Virus. The illness caused by this infection is named HGRAD- Human Gamma Retrovirus Associated Disease.

We plan to announce this at the upcoming NIH retroviral conference this September.

Definitely stay tuned- the volume of new and important information about this virus and its disease associations is increasing rapidly and in my opinion should be a concern to every patient with chronic neuro-immune diseases, including those with chronic Lyme. [12]

It sounds like some exciting findings may be on the way.

Conclusion

This case is a fascinating illustration of the twisting turns that scientific research can take. The early discovery of a link between anti-viral immunity and prostate cancer may now lead to a cure for chronic fatigue syndrome. At least, we can hope so.

As one of the pioneers, Dr. Robert Silverman, describes it,

One of the remarkable aspects of being a scientist, is that you never know where your scientific journey will lead. [1]

Science takes a lot of patience, diligence, and persistence. It’s gratifying when all that work is rewarded by discovery.

References

[1] Silverman RH. A scientific journey through the 2-5A/RNase L system. Cytokine Growth Factor Rev. 2007 Oct-Dec;18(5-6):381-8. http://pmid.us/17681844.

[2] Suhadolnik RJ et al. Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome. J Interferon Cytokine Res. 1997 Jul;17(7):377-85. http://pmid.us/9243369.

[3] Silverman RH. Implications for RNase L in prostate cancer biology. Biochemistry. 2003 Feb 25;42(7):1805-12. http://pmid.us/12590567.

[4] Casey G et al. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat Genet. 2002 Dec;32(4):581-3. http://pmid.us/12415269.

[5] Carpten J et al. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet. 2002 Feb;30(2):181-4. http://pmid.us/11799394.

[6] Urisman A et al. Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006 Mar;2(3):e25. http://pmid.us/16609730.

[7] Lombardi VC et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009 Oct 23;326(5952):585-9. http://pmid.us/19815723.

[8] Switzer WM et al. Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States. Retrovirology. 2010 Jul 1;7:57. http://pmid.us/20594299.

[9] Lo S et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. PNAS Epub before print August 23, 2010. http://www.pnas.org/content/early/2010/08/16/1006901107.abstract.

[10] Amy Dockser Marcus, “New Hope in Chronic Fatigue Fight,” Wall Street Journal, Aug 23, 2010, http://online.wsj.com/article/SB10001424052748703846604575447744076968322.html.

[11] David Tuller, “Study Links Chronic Fatigue to Virus Class,” New York Times, Aug 23, 2010, http://www.nytimes.com/2010/08/24/health/research/24fatigue.html.

 [12] http://www.forums.aboutmecfs.org/showthread.php?7001-News-from-WPI-symposium-Name-change-to-be-proposed-for-XMRV (hat tip http://health.groups.yahoo.com/group/infection-cortisol/message/1753).

Leave a comment ?

27 Comments.

  1. Hi Paul,

    You might want to look into the links between CFS and adrenocorticotropin hormone (ACTH) deficiency. I’ve seen plenty of evidence that CFS could potentially be an autoimmune disease of the hypothalamus or pituitary.

  2. Paul, I’m in awe of the depth of your knowledge on such a wide variety of subject.

  3. Hi Robert,

    Thanks for the suggestion, I’ve put it on my to-do list. Do you have a link to an introduction? As neither I nor any of my family and friends have had CFS, I’m not as deep into its literature as some other diseases.

    erp, thank you, but my erudition comes from the same source as Samuel Johnson’s wit. I steal.

  4. Wherever it comes from, it’s awesome.

  5. extremely fascinating, and great blog post!

  6. paul, i know that people with CFS and FM often tremendously benefit from http://www.lowdosenaltrexone.org

    it seems to be a stron immune modulator or something.
    could be an additional piece of the puzzle.

  7. This is a review on the status of the adrenals and its relationship to CFS:

    http://www.ncbi.nlm.nih.gov/pubmed/15036250

  8. Thanks Robert. One thing I learned at cpnhelp.org is that many people with chronic illnesses have disrupted thyroid and adrenal axes. But the question is whether these are causes or symptoms of the disease.

    One wildcard is that infections of the thyroid can cause both hyperthyroidism and hypothyroidism; I imagine the adrenal glands can be infected also and suffer impairment by that route.

    There are some papers suggesting that infections elsewhere, e.g. hepatitis C, can cause circulating cytokines to damage the hypothalamus, e.g. http://www.ncbi.nlm.nih.gov/pubmed/12946286. I’m not a believer in action-at-a-distance in biology, but maybe.

    Regarding autoimmune possibilities, my general prejudice is that they’re mostly the result of infections and tend to disappear soon after the infection. One review of CFS states that “Immune dysfunction as the cause of CFS is thus far the weakest hypothesis” (http://www.ncbi.nlm.nih.gov/pubmed/17853290) and since that agrees with my prejudices I will believe it pending further investigation. 🙂

    I have resisted delving into adrenal biology but I’ve noticed that a growing number of people in the blogosphere, e.g. Matt Stone, seem to think it’s the key to everything.

  9. qualia,

    Thanks. Low-dose naltrexone seems like a wonder drug, and Dr. Bihari’s discovery is a heart-warming story. Figuring out to try a subpharmacological dose between 2 am and 4 am has to be one of the cleverest ideas of recent medicine; and rarely does a clinical practitioner come up with an innovation and get it widely adopted and investigated without any funding or research support.

    I might be able to do a blog post on it after the book is out. I’ll be a little swamped until then.

  10. Paul,

    Have you looked into any of the subsequent literature about XMRV? It seems highly likely at this point that it was a result of contamination:

    http://en.wikipedia.org/wiki/Xenotropic_murine_leukemia_virus-related_virus#Contamination_and_artifact

    Will

  11. What do you know about the use of cimetidine/ tagamet as immune booster and energizer for chronic fatigue?

  12. I was doing better on PHD for a while, and then I keep getting sick. I went to a chronic fatigue doctor and tested positive (high IgG, which indicates a past infection, rather than high IgM, which would indicate an active one) for a lot of viral infections – Epstein-Barr, Cytomegalovirus, Herpes Simplex 1 or 2, and maybe even C. Pneumoniae. Some of the things I’ve noticed is that my taste for protein is lower than it was when I started eating a paleo/primal type diet. I know protein restriction can help with viruses, so hopefully listening to my body is good.

    Also, it’s very, very hard for me to intermittently fast. When I do so, I find that I get so tired after I eat that I am completely useless. Finally, Vitamin C is one of the few things that really helps me – I feel great on days when I take upwards of 8 g (I think the last time I tested to bowel tolerance it was around 40 g at first, then later around 36 g). Why aren’t more doctors willing to prescribe antivirals and run the type of tests which my chronic fatigue doc ran for me, but are very willing to prescribe antibiotics?

  13. Hi Paul,

    Do you have any new thoughts and recommendations concerning “chronic fatigue syndrome” these days? I’m reading some of your old posts with interest, and am wondering about IF vs. ketogenic diets vs. ??? for my husband, who has suffered from autoimmune issues all of his life, with worsening fatigue and “wasting” type of symptoms recently…

    Thanks so much,
    Sarabeth

    • Hi Sara,

      I strongly recommend IF and do not recommend a ketogenic diet. Try to concentrate his food intake in a narrow window in the afternoon, and take no calories during a 16-20 hour overnight fast except black coffee, green tea, and maybe some salted bone stock and vegetables soup to lessen the stress of the fast. Work on circadian rhythm entrainment, sunshine and daily exercise. Eat plenty of PHD food though during the feeding window, with emphasis on supplemental foods like liver, egg yolks, spinach, seafood, potatoes.

  14. Hi Paul, I am an exercise physiologist with a client who has chronic fatigue syndrome – I have lent her a copy of your book and have prescribed a graded exercise program. She has recently decided to purchase this frequency generator zapper device that is supposedly designed to kill parasites http://www.huldaclarkzappers.com/
    It looks dodgy to me, but I don’t have the knowledge to tell her not to waste her money – especially because she is at her wits end. I would be pleased to hear your views.

  15. Hi Paul, where do we go for chronic infection testing located outside of the gut? Lyme doc perhaps? I’m wanting to get a comprehensive analysis of any systemic pathogens I may have. Most doctors are completely uneducated about such things. I’m 20 years old and have extreme fibromyalgia. All of my muscles, tendons, and ligaments are affected as well as my joints. Seems like my whole body is calcified. Blood flow is incredibly sluggish. This happened after a 5 month course of accutane and an extremely stressful lifestyle. Have been on your diet for the past year and a half (modified to eliminate any potential foods that don’t agree with me). Thanks

  16. Paul,
    After much pain and suffering I have been diagnosed with Lyme disease. So you have any thoughts as to keep healthy during treatment? And would cutting carbs lower be better For this kind of disease?
    Thanks a lot for everything you do!

    • Hi Keven,

      Intermittent fasting and circadian rhythm entrainment are crucial. You could try extending the daily fast beyond 16 hours, e.g. feast for 3 hours in the early afternoon and then fast for 21 hours. I would stick with 30% carbs.

      Best, Paul

  17. Hi Paul!

    I’ve recently been diagnosed with CFS, and I found your article very interesting! Whilst research into CFS definitely could move quicker, I’d be interested to hear your take on how the science has progressed over the last six years. Is XMRV still a being considered? I find it all somewhat overwhelming, and I’m about to spend ££££ on a bunch of tests for Lyme, EBV, CMV, etc., but XMRV or Human Gamma Retrovirus has not been mentioned to me. Any insight would be very much appreciated!! Many thanks for your great work!

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