30 August 2010

Not just XMRV anymore.

In October, 2009, a paper by Lombardi, V., et al., ‘Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome’ was published in a leading   research journal, ‘Science’. This paper demonstrated evidence that a Murine Leukemia Virus (MLV) species, XMRV, was associated with ME/CFS in some (yet to be determined) manner, with the results showing the virus was present in 95% of CFS patient samples (Lombardi, V., et al., 2009).  This study also found that the XMRV virus was present in 4% of the healthy control samples (Lombardi, V., et al., 2009).

In January 2010, a paper by a group of UK scientists, from both the Faculty of Medicine of the Imperial College and Department of Psychological Medicine, Institute of Psychiatry, Kings College, published findings that failed to identify any association between XMRV and ME/CFS (Earlwin, et al,. 2010). This paper, Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome, was published in the Public Library of Science, is discussed briefly in the blog entry dated 07 January 2010. 

In February 2010, another study came out of the UK, which again failed to find an association between XMRV and ME/CFS.  The findings of the Groom, H., et al (2010) paper, Absence of xenotropic murine leukemia virus-related virus in UK patients with chronic fatigue syndrome, were published in the journal Retrovirology.  The results of this paper are discussed in the blog entries dated 20 February 2010 and 25 April, 2010.
In the Netherlands, Kupperfield, F., et al (2010), published ‘Prevalence of xenotropic murine leukemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort’ in the British Medical Journal.  Again, this study failed to identify XMRV in the CFS samples used in the research (Kupperfield, F., et al. 2010).

Increasingly, during the period of time since the publication of the Lombardi, V., et al., (2009) paper, patients, families, carers, medical professionals, researchers, have debated the possibilities for such conflicting results.  Judy Mikovits at the WPI, stated that XMRV was notoriously hard to find, stating that the virus is
'...in too low a copy number in the genomic DNA (that is the provirus..integrated into the cells DNA) ..there may be less than 10 copies of provirus in 10 million cells..so unless you amplify the 1 microgram of genomic DNA from uncultured cells you might miss it' (Johnson, C., 2010).

Further to this, press releases from the Whittemore Peterson Institute detailed differences in the way the experiments were carried out which demonstrated why these studies were not true replications of the Lombardi, V., et al., (2009) study.  The Whittemore Peterson Institute sent a letter specifically to Dr Myra McClure, of the Earlwin, O., et al (2010) paper, suggesting that differing techniques and equipment were being used, as well as ME/CFS sample cohorts defined by criteria different to that which the Whittemore Peterson Institute used.  A discussion of this is available in the blog entry posted 20 Feburary, 2010.

On the 22 of June, 2010, a press release was published which stated that a combined team of scientists from the Food and Drug Administration, (FDA) and the National Institutes of Health, (NIH), had completed a replication of the Lombardi, V., et al., (2009) study, which not only confirmed the original findings, but expanded on them. It was soon announced, however, that due to conflicting results with a paper published by the CDC, a halt was placed on the Lo, S., et al (2010) publication.  Again, debate about the studies was further fuelled by involved parties; researchers, patients, doctors, and support organisations.

At 7am, New Zealand time, on August 24, the press embargo was lifted, and the Lo, S., et al (2010) paper was finally available online.

Lo, S., et al (2010) used 37 whole-blood and serum samples which had been collected from individuals with ME/CFS in the mid 1990's.   Lo, S., et al (2010)  also obtained repeat blood samples from 12 of the initial 37 patients; 4 of which were collected two years after the first samples were taken, and the remaining 8 were collected again in 2010.  Alongside this, blood samples were collected from 44 healthy controls.  Lo, S., et al (2010) reported that they used nested PCR techniques to target the gag gene of any XMRV DNA sequences present, as well as other MLV-like DNA.

The results of the Lo, S., et al (2010) demonstrated that 32 of 37 (86.5%) samples from ME/CFS patients revealed positive amplification of MLV-like viral gene sequences in the nested PCR, compared with  3 of 44 (6.8%) volunteer blood donors.  On testing of the 8 repeat samples collected in 2010, 7 remained positive, although all 8 reportedly remain symptomatic. 

In reading the results and discussion of the Lo, S., et al (2010) paper, one thing becomes glaringly obvious.  The results fail to report any specific findings of XMRV, that mouse virus variation which many people have taken great pains to undertsand over the past several months.  Instead, Lo, S., et al (2010) reports finding MLV's, (Murine Leukemia Viruses), which are a genus of gamma retroviruses, of which, XMRV is a species.  In fact, Lo, S., et al (2010) identified 4 variations of MLV's, not all of them xenotropic (warranting the XMRV label).  Judy Mikovits reports presenting a paper at the Cold Spring Harbor RNA tumor virus meeting in May 2010 demonstrating samples in the Lombardi, V. et al (2009) paper had Xenotropic (as in XMRV) and polytropic MLV variants as well as at least one more variant.  (Ketei, M., 2010). Furthermore, in comparing the 8 samples collected in 2010 with samples collected from the same 8 individuals with ME/CFS 15 years ago, it was apparent that the MLV had gone through significant mutation (Lo, S., et al. 2010).  “That’s just what you’d expect from a retrovirus,” said Alter. “That’s more evidence that this is a real agent, not a sequence floating around in the lab.” (Ketei, M., 2010).

Aside from the different variations of MLV identified in the Lo, S., et al (2010) publication, is the startling evidence that almost 7% of the controls, all of whom are blood donors, tested positive for these MLV variants.  This is indicative that these variations of MLV's are likely in the public blood supply, at least in the USA, where the samples were taken.  Mindy Kitei, of CFS Central, reports that Harvey Alter is commencing studies to determine if the MLVs identified in the Lo, S., et al (2010) paper, are potentially transmitted by blood (Ketei, M., 2010).

It is important to state that at this stage, there is not sufficient evidence to suggest MLV's are causative or co-morbid pathologies to ME/CFS.

News of the publication of the long awaited Lo, S., et al (2010) paper spread quickly across the internet, with discussions, blog posts, news articles and opinions being printed and reprinted through social mediums such as facebook.  It appears, however, that in some areas of the world, namely the UK, the news has been much slower off the press. Andrea Pring, writer and fellow ME/CFS patient, reports on her blog, Dancing with the Sandman, some of the contextual factors possibly contributing to the lack of news coverage in the UK, including the involvement of Professor Simon Wessley in the advisory panel of the Science Media Centre (Pring, A., 2010).  For further detail on this, please read Andreas blog post titled 'The Truth Behind the Headlines (August 29, 2010).

I would now like to take this opportunity to print a public thank-you to all the researchers, medical professionals, advocates, organisations, carers, families and supporters who have worked tirelessly over the decades, in the search for explainations and answers to this illness. It is far from over; the exploration continues, but we can be graterful of the advance in knowledge of this disease that has been made in the past few months.

Specifically, I woould like to thank Annette and Andrea Whittemore; Annette, in her quest as a mother to give her daughter the opportunity of quality of life and improved health, has given hope of a greater quality of life and health to all sufferers of ME/CFS across the globe.  And Andrea, in advocating for her own health, as well as advocating for the work of the Whittemore Peterson Institute, has given a voice to all ME/CFS patients, worldwide.  For this, we thank you both.

References:

"Detection of MLV-related virus gene sequences in blood of patients with Chronic Fatigue Syndrome and healthy controls,"

Erlwein, O., Kaye, S., McClure, M., Weber, J., Wills, G., Collier, D, Wessely, S., and Cleare, A., (2010). Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome.  Retrieved 29 August 2010 from: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008519.

Frank J M van Kuppeveld, Arjan S de Jong, Kjerstin H Lanke, Gerald W Verhaegh, Willem J G Melchers, Caroline M A Swanink, Gijs Bleijenberg, Mihai G Netea, Jochem M D Galama, & Jos W M van der Meer (2010). Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort British Medical Journal : 10.1136/bmj.c1018

Groom, H., Boucherit, v., Makinson, K., Randal, E., Baptista, S., Hagan, S., Gow, H., Mattes, F., Breuer, J., Kerr, J., Stoye, J., Bishop, K. (2010) Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 7:10. Retrieved August 2010 from http://www.retrovirology.com/content/pdf/1742-4690-7-10.pdf

Johnson, C., (2010).  A Different Kind of XMRV? Dr. Mikovits and Dr. Racaniello on XMRV. Retrieved August 2010 from http://www.forums.aboutmecfs.org/content.php?187-Dr-Mikovits-and-Dr-Racaniello-on-XMRV
Pring, A., (2010). Dancing with the Sandman: The Truth Behind the Headlines. Retrieved August 2010 from http://dancingwiththesandman.blogspot.com/2010/08/truth-behind-headlines.html

Switzer, W. M.; Jia, H.; Hohn, O.; Zheng, H.; Tang, S.; Shankar, A.; Bannert, N.; Simmons, G. et al. (2010). "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 7 (1): 57. doi:10.1186/1742-4690-7-57. PMID 20594299.

5 comments:

  1. Today no one needs to suffer with CFIDS, treatment is already known www.cfids.info

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  2. Thanks for a well written summary of events. I look forward to hearing Mikovits report at the Workshop next month. Keep up the good work!

    xxx

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  3. I second your heartfelt thanks to our researching heroes!

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  4. Wonderful blog EK. You do a fantastic job of making things clearer for us. Thank you also to Annette and Andrea. The future is a little more positive because of them.

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  5. 3 September
    Emma-Kate, are you OK? Just read about the 7.2 earthquake in New Zealand near Christchurch. Please make a short post to let all of your friends and fans on the other side of the world know you're safe and well. You're in our thoughts and prayers. Be safe!

    ReplyDelete