The National Insitutes of Health (NIH) has recently updated two pages on its website with new information about XMRV based on two studies published on May 31, 2011, in the journal Science that cast further doubt on an association between the retrovirus and human disease. The information affirms plans to continue with two multicenter studies in which the Whittemore Peterson Institute and other laboratories are participating.
From the Trans-NIH ME/CFS Working Group’s Frequently Asked Questions page:
14. Where do the latest findings from NCI that an association between XMRV and chronic fatigue syndrome (CFS) is due to laboratory contamination put the XMRV interested/involved communities?
Although it appears that XMRV (xenotropic murine leukemia virus-related virus) is a contaminant and not associated with human disease, the National Institutes of Health (NIH) continues to fund studies to determine whether results of recent studies can be replicated. Additional information will be gained from the completion of two large studies (Lipkin, National Institute of Allergy and Infectious Diseases) and the Blood XMRV Scientific Research Working Group (National Heart Lung and Blood Institute) that were initiated to study any potential connection between XMRV/MLV and human health or risks to the blood supply. In addition, the NIH funds and will continue to fund peer reviewed, investigator-initiated research that seeks to understand the role that viruses, including retroviruses, play in the etiology of a variety of human diseases.
15. Do people with CFS have to go back to the drawing board?
Scientists and clinicians are following a well-respected path of research, whereby hypotheses are proposed, tested, and then validated or refuted. This path continues as the research communities try to identifya cause of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
16. Is there still uncertainty regarding XMRV’s role in CFS?
The body of evidence now indicates that XMRV does not play a role in ME/CFS. However, that does not preclude the need to replicate and confirm the results of recent studies, which could uncover other associations between ME/CFS and human pathogens.
17. Is there additional research planned/underway?
Although it appears that XMRV is a contaminant and not associated with human disease, NIH continues to fund studies to determine whether results of this study can be replicated and the lack of association between XMRV and ME/CFS confirmed. Additional information will be gained from the completion of two large studies (Lipkin, NIAID) and the Blood XMRV SRWG (NHLBI) that were initiated to study any potential connection between XMRV/MLV and human health or risks to the blood supply. In addition, the NIH funds and will continue to fund research that seeks to understand the role that viruses, including retroviruses, play in the etiology of a variety of human diseases.
18. Does the NIAID intend to continue to support the Lipkin study?
Yes. This laboratory-based study is designed to rigorously evaluate whether the presence of XMRV/MLV nucleic acids in the blood is associated with CFS. Researchers, working with clinicians in six regions across the United States, will compare blood and plasma samples from patients diagnosed with CFS to samples from healthy people who have not been diagnosed with CFS and who are matched to the CFS patients by age, sex, and geography. Study results are anticipated later this year.
19. Does NHLBI intend to continue to support the XMRV blood study?
Yes. This study will compare results from participating laboratories across the country and improve our understanding of the assays in use. Results from this study, expected in the Fall of 2011, will help determine whether XMRV and other related viruses represent a potential threat to the safety of the blood supply.
XMRV is currently featured on the NCI's home page
From the National Cancer Institute’s Page: XMRV and Human Disease: Questions and Answers
4. What steps did NCI and other researchers take to arrive at a better understanding of XMRV’s possible role in disease causation?
2009: NCI convened an international meeting of scientists in July 2009 to discuss potential public health implications of XMRV. During this meeting, evidence was presented that suggested a link between XMRV and CFS. This evidence pointed to an immediate need for development of rapid and accurate diagnostic tools and methods to identify and analyze XMRV. NCI’s Frederick, Md., laboratories established a XMRV action plan with the responsibility for producing the necessary research tools in both quality and bulk; established reproducible diagnostic platforms; and made their tools, technologies and expertise available to researchers in the broader scientific community, with a goal of undertaking large-scale epidemiological studies.
2010: NCI-produced tools were made available to outside researchers through the NIH AIDS Reagent Repository (see https://www.aidsreagent.org/Index.cfm). At the same time, independent studies were initiated within NCI to determine whether XMRV was in people who had been diagnosed with CFS or prostate cancer. If a link was found, the goal was to try to establish whether the virus played a role in either condition and, if so, to determine whether antiretroviral therapies that are effective against HIV would display broad-spectrum activity against XMRV as well. NCI was the first to show that in addition to the anti-HIV agent AZT (one of the first drugs used against HIV), tenofovir and raltegravir potently inhibited XMRV replication.
2011: In contrast to previous findings, and in keeping with reports that subsequently emerged in the literature, two independent NCI studies failed to detect XMRV in humans. In other studies, it was observed that XMRV replication is severely inhibited in human white blood cells, making it doubtful that XMRV replicated efficiently in the blood cells of CFS patients as previously reported. Additional evidence was obtained showing that previous data was potentially confounded by the presence of contaminating mouse DNA, and/or by contamination with XMRV virus in the laboratory.
5. What conclusions can now be made about XMRV and human disease?
Recent studies from NCI and Tufts University laboratories have shown that XMRV originated by recombination between two mouse viruses when human prostate tumors were grown in mice in the mid 1990s as part of experiments to develop an animal model system of human prostate cancer. Because all XMRVs that have been isolated and genetically sequenced are extremely similar to the virus that arose in this original recombination event, they are most likely to be laboratory contaminants derived from this recombinant virus. Using highly-sensitive XMRV DNA detection techniques (similar to those that have become the gold standard for HIV), coupled with methods to detect mouse DNA, NCI researchers tested new, independently-collected serum samples from a small selection of patients reported to be infected in the original 2009 Science publication that hypothesized a connection between XMRV and CFS. This analysis indicated significant levels of mouse DNA contamination in several of these samples; however, there was no evidence that any of the people tested a second time had been infected with XMRV. In addition, a sample of the XMRV viruses reported in the 2009 article has been cultivated from patient samples and was analyzed at NCI. In contrast to the original findings, the new data suggest it is unlikely that these XMRVs were derived from infected patients. Instead, like the other XMRVs that have been sequenced, they appear to be laboratory contaminants.
The NCI study is being reported in the same issue of Science as another study of XMRV (Knox et al.) that finds a lack of association between the virus and CFS even in the same patients from a 2009 study.
6. Can a role for viruses in causing prostate cancer or CFS now be ruled out?
While studies now cumulatively and convincingly exclude a role for XMRV in prostate cancer and CFS, they do not rule out the possibility that some other virus or viruses might play a role in either disease. It is known that a variety of viruses contribute to about 15 percent of known human cancers.
References:
Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung H, Tepper CG, Hu W, Fivash Jr. MJ, Coffin, JM, and Pathak VK. Recombinant Origin of the Retrovirus XMRV. Science. Online May 31, 2011.
Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett Jr. J, Qiu X, Luk K, Schochetman G, Knox A, Kogelnik AM, and Levy JA. No Evidence of Murine-like Gammaretroviruses in CFS Patients Previously Identified as XMRV-infected. Science. Online May 31, 2011.
Shin CH, Bateman L, Schlaberg R, Bunker AM, Leonard CJ, Hughen RW, Light AR, Light KC and Singh IR. Absence of XMRV and other MLV-related viruses in patients with Chronic Fatigue Syndrome. J Virol. May 4, 2011. doi:10.1128/JVI.00693-11
Coffin JM and Stoye JP. A New Virus for Old Diseases? Science. 2009. 326:530-531.
Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N, Denner J, Miller K, Kurth R, and Bannert N. Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology. 2009. 6:92.
Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, and Mikovits JA. Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science. 2009. 326: 585-589.
Schlaberg R, Choeb DJ, Browna KR, Thakerb HM, and Singh IR. XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. PNAS 2009. 106: 16351–16356.
Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL. Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant. PLoS Pathogen. 2006 2:211-225.
Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H, Aepfelbacher M, Schlomm T. Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. JClin Virol. 2008. 43:277-283.
D’Arcy F, Foley R, Perry A, Marignol L, Lawler M, Gaffney E, Watson R, Fitzpatrick J, and Lynch T. No evidence of XMRV in Irish prostate cancer patients with the R462Q mutation. European Urology Supplements. 2008. 7:271.
Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu W-S, and Pathak VK. Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J. Virol. 2010. 84: 5719-5729.
Chaipan, C, Dilley, KA, Paprotka, T, Delviks-Frankenberry, KA, Venkatachari, NJ, Hu, W-S, and Pathak, VK. Severe restriction of xenotropic murine leukemia virus-related virus replication and spread in cultured human peripheral blood mononuclear cells. J. Virol. 2011. 85: 4888-4897.
Aloia AL, Sfanos KS, Isaacs WB, Zheng Q, Maldarelli F, De Marzo AM, and Rein A. XMRV: A new virus in prostate cancer? Cancer Res. 2010. 70: 10028-10033.
Li M, Dimaio F, Zhou D, Gustchina A, Lubkowski J, Dauter Z, Baker D, Wlodawer A. Crystal structure of XMRV protease differs from the structures of other retropepsins. Nat. Struct. Mol. Biol. 2011. 18: 227-9.
Note: This material was copied directly from the NIH website on June 5, 2011. See pages http://orwh.od.nih.gov/CSF%202011/faq.htm and http://www.cancer.gov/newscenter/qa/2011/xmrv_qa.
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Wow. These are heavy duty statements from NCI and the Trans-NIH Working Group. I hope that any additional data that is unpublished will be made available to the public so we can understand what it happening.
All any of us want is the truth. However, the recombinant theory does not stand up. When the Alter/Lo paper found HGRV’s in 85% of the ME/CFS cohort, it was said that they were too divergent from XMRV by the very people who are now claiming little diversity supports the recombinant event. Lo also found the retrovirus to have mutated in patients from the initial sample, taken 15 years ago, to the fresh samples they drew for their Aug. 2010 study.
http://vimeo.com/24683179
The link I give above shows how very sick 25% of us are. These are the ones too ill to respond online. This fact, I believe, is not commonly known among those that hold our fate in their hands. That, plus the dustbin diagnosis achieved by the Fukuda and CDC criteria have obfuscated research into ME/CFS for too long. The only criteria in current use that is tight enough is the Canadian.
This illness costs America $20 – $50 billion annually in lost productivity. Please allow all branches of research to go forward, and support the WPI in their scientific endeavors. They have done more to raise the profile of this devastating disease in a few short years than anyone else has in the last few decades.
Jane,
I think the sequence similarity of XMRV and sequence diversity of the Alter/Lo MLV’s are two different discussions. Alter and Lo’s MLV sequences are distinct from XMRV and are in and of themselves a fairly divergent group. XMRV is a distinct virus from the Alter/Lo sequences and other MLV’s, which at the time supported the notion that it was simply not mouse contamination mucking up the experiments. However with the discovery that XMRV is a common lab contaminant itself, things became more unclear. Since the original findings were published, the extreme similarity of XMRV sequences and the fact that phylogenic analysis has reported that the 22rv1 virus is ancestral to purported patient derived sequences now actually work against XMRV being a circulating human pathogen.
As for Lo’s MLV sequences and his reported finding of sequence evolution in his patient population, there are several new findings (some published, some not) which cast much doubt on these findings as well.
At the recent NIH ME/CFS State of the Knowledge workshop, Dr. Coffin’s presentation (1) touched on the Alter/Lo MLV issue in which he stated the following- “So if we go back to our phylogenetic tree now (slide) and we put in these green dots- the samples that the Huber study found, we find that they just sort of plop all over this tree, more or less randomly- there may be a little concentration here but more or less randomly distributed across the tree. Here are all of the XMRV sequences for reference, here by the way (black dots). These again are quite similar, not identical but very similar to one another.
If we now look at Mary Kearney, a colleague at NCI Frederick, she did an experiment where she deliberately took very very small amounts of DNA, she took 1/30th of a cell and distributed 1/30th of a cell over a lot of wells, amplified the DNA that was in there, sequenced those amplification products and so this is what you’d find from low level, deliberate contamination with mouse DNA (blue dots). You tell me if that looks different, really different in any significant way from this (referring to slide). And this for comparison is what was in the Lo et al study (red dots), again I don’t see any difference between any of these and I just can’t come up with any explanation for this pattern of sequences unless it really is due to that.”
(slide)- http://i56.tinypic.com/snp9vm.png
There is also a recent paper which reported basically the same thing from a slightly different starting point, ‘PCR Master Mixes Harbour Murine DNA Sequences. Caveat Emptor!’(2), in which the paper both identifies sequences in PCR master mixes which almost exactly match the Alter/Lo MLV’s, including some which the authors state are replication incompetant (big red flag, if the ‘virus’ is replication incompetant how could it infect anybody?), as well as calls into question whether the repeat testing sequences done by Alter/Lo (which were taken from 8 patients whose samples were included in the original study and which were retested) could even come from the original sample sequences- “The exact variety and nature of our sequences show very close parallels to those reported by Lo and colleagues from patients with CFS especially in the set of samples from recent repeat isolations. They argue that the recent sequences (MLV001–MLV006; HQ601957–62) show evidence of viral evolution from an earlier sequence (assumed here to be cfs1 since this was identified in 18/21 sequences). However such evolution would be predicted to show monophylogeny. Our maximum likelihood analysis of these sequences is clearly inconsistent with such a prediction. In particular we see no obvious explanation for a sequence of the modified polytropic cfs1 type evolving into a polytropic sequence like MLV002 or MLV006, Similarly it seems implausible that MLV001, which shares with 9C a deletion encoding 15 amino acids of matrix (MA), presumably precluding virus replication, could evolve from cfs1. In the absence of evidence for replication competent MLV in the samples reported by Lo and colleagues, we believe that the finding of a population of gag sequences in the reagents, as well as the coincidence of a virtually identical replication incompetent MLV in our study and that of Lo and colleagues, must call into question the biological provenance of these sequences and therefore any conclusions drawn concerning their relationship to CFS.”
1. NIH ME/CFS State of the Knowledge Workshop- http://videocast.nih.gov/Summary.asp?File=16575 (Coffin presentation starts at 154:00, Mikovits presentation is immediately prior in case you might be interested)
2. PCR Master Mixes Harbour Murine DNA Sequences. Caveat Emptor!-
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0019953
John…. As I write this there is an International Retrovial Conference/group meeting in Amsterdam that is talking about XMRV in detail. Please stay tuned.. Nila