TWiV 98: Murine musings, electric shirts, and rabid pathologists

September 12, 2010

Hosts: Vincent Racaniello, Alan Dove, and Rich Condit

Vincent, Alan, and Rich review the finding of murine leukemia virus-related sequences in the blood of CFS patients and healthy donors, laboratory inventories for wild poliovirus containment, weaving high-performance viral batteries into fabric for the military, and a case of human rabies in Indiana.

Click the arrow above to play, or right-click to download TWiV #98 (58 MB .mp3, 80 minutes)

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  • Virus newbie

    Thank you for the discussion on the Lo/Alter study! It helped me understand more about the paper, but also raised new questions. Specifically, what is the significance of XMRV as a recombinant? TWiV Virology 101 has taught me about 3′ and 5′ ends, but how does a recombinant come to be? Is it common? Does it tell us anything more about XMRV? I was also confused by the discussion about glyco-gag, both in terms of what glyco-gag is/does and the significance of the XMRV glyco-gag being identical to glyco-gag in a lab strain of mice. Maybe you can address my newbie confusion in a future show.

    Thanks for this brilliant podcast. I am learning so much from all the TWiVs!

  • LC

    Dr Anthony Komaroff, who provided some patients for the PNAS paper, did confirm to Mindy Kitei that of the 8 patients retested, all of them remained sick.

    “In addition, the blood from eight of the 25 patients Komaroff supplied from 15 years ago had blood draws again in March 2010. Seven of the eight remained positive. According to Komaroff, the patient who became negative hadn’t recovered.” CFS Central http://www.cfscentral.com/2010/08/fdanihharvard-xmrv-study-same-thing.html

  • Eric

    Thanks Dr. Racianello and co-hosts for this programme. Regarding the question wheter the Lo, Alter et al. study confirms the Lombardi, Mikovits et al. study (“Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome”) Dr. Alter stated in the press briefing on 8/23 that his study is “highly confirmatory” of “Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome”. I can’t find the link to the audio file right now, but here’s a transcript http://www.facebook.com/note.php?note_id=432527206796. As far as i know Dr. Alter is working on a study involving samples of around 1000 persons, this will be interesting.

    Eric

  • LC

    The issue of clinical trials came up in your podcast, I thought you may like to know that CFS patients are known to have a low placebo response.

    http://www.medscape.com/viewarticle/538172
    http://www.psychosomaticmedicine.org/cgi/content/full/67/2/301

  • LC

    Many CFS patients, just like prostate cancer patients, will also be too sick for a follow up. And because of the variety of symptoms that they experience, they are not necessarily going to be able to tell whether they are on placebo.

  • http://www.cfids.org Kim McCleary

    Hi TWiV guys: Thanks for following the evolving story of XMRV, MLVs (PMRV) and CFS. You questioned whether the 8 patients who were retested in the PNAS paper after 15 years were still ill. Here’s an excerpt from our Q&A with experts, including physician Anthony Komaroff, MD at Harvard, in which he answers a related question:

    Q: Do the three variants of MLVs found in the CFS patients from your practice correlate to any particular CFS symptoms, type of onset, age, illness severity, etc.?

    A: Not that we can tell, but the total numbers are small. We need much larger studies to answer this important question. — Anthony L. Komaroff, MD, The Simcox/Clifford/Higby Professor of Medicine, Harvard Medical School; Editor in Chief, Harvard Health Publications, Harvard Medical School; and Senior Physician, Brigham and Women’s Hospital

    Listeners can find the Q&A about the PNAS study, XMRV, MLVs, etc. at http://www.cfids.org/cfidslink/2010/090104.pdf and other resources at http://www.cfids.org/mlv/default.asp

  • Robin

    To Alan Dove: researchers found XMRV in people with prostate cancer. Initially it was thought to be associated with deficiency in RNASEL antibody, that has since been proven to no longer be the case. That was mentioned in a different episode of twiv where the guest was Ila Singh.

    Dr. Mikovits of the original Science began examining patients for viral replication using a virochip, and found an unidentified virus with the same signature in a lot of patients. Because some CFS patients also have RNASEL deficiencies, the link was made and she began looking for it patient’s blood and plasma. This was obviously before the RNASEL/XMRV theory was abandoned.

  • Kim McCleary

    You also discuss the need to look for XMRV/MLVs in other disease groups in addition to prostate cancer and CFS. Based on published studies, evidence of infection with XMRV has also been looked for in samples obtained from men with HIV, men at risk for HIV infection, individuals with ALS, individuals with spondyloarthritis and children with idiopathic diseases. So far, in these limited studies, no XMRV has been found. A group of researchers in Germany reported finding XMRV-specific sequences in 2-3% of 168 samples from immunocompromised carriers and about 10% of samples from 161 immunocompromised patients. As you state in episode #98, negative studies may need to be repeated with primers that are able to detect a wider variety of virus strains, based on the findings of Lo/Alter. (http://www.cfids.org/xmrv/default.asp)

  • LC

    One of the reasons for the different results, that is being considered, is the preparation of samples. This was mentioned at the Q&A of the International XMRV conference.

    The reason that the WPI checked CFS patients for XMRV, was because of the same immune defect that XMRV initially seemed to correspond with in prostate cancer patients. This was later shown to be irrelevant to XMRV infection, and therefore it is hardly a stroke of luck that they looked in two disease and found it.

    The authors of the PNAS paper into CFS also stated that the virus, in patients tested 15 years later, had mutated.

    “Important to note is the retroviruses detected in those seven patients in 2010 had mutated in the 15-year interim. “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.” CFS Central http://www.cfscentral.com/2010/08/fdanihharvard-xmrv-study-same-thing.html

    If you do go out and collect wild mice, you may want to be careful, you don’t want to catch anything. :-)

  • LC

    And with a different sample preparation method.

  • LC

    Sorry that should say, the one who tested negative remained sick.

  • V77

    http://www.cfscentral.com/2010/08/fdanihharvard-xmrv-study-same-thing.html
    “In addition, the blood from eight of the 25 patients Komaroff supplied from 15 years ago had blood draws again in March 2010. Seven of the eight remained positive. According to Komaroff, the patient who became negative hadn’t recovered.”

    Negative patient still sick.

    http://www.mecfsforums.com/index.php More information here.

  • John

    The issue of criteria is really a question of ideology, competance, and perhaps integrity as opposed to purely scientific variables.

    The 1994 CDC Fukuda criteria is as follows (paraphrased)- Severe fatigue which results in substantial reduction in activity for 6 months; must be of new onset, ie cannot be lifelong (although children can and do become ill with CFS). This ‘fatigue’ must be accompanied with 4 of 8 additional symptoms- substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise(PEM) lasting more than 24 hours.

    What the authors of the Canadian Criteria did was to make post-exertional malaise, sleep disturbances and impaired concentration/neurocognitive difficulties mandatory as opposed to them being optional, as these three (and most importantly the first, PEM) are the quintessential hallmarks of the illness, and the diagnosis should not be made in their absence.

    However as you can see, with the Fukuda criteria, a researcher (most commonly a member of what CFS patients refer to as the ‘psychosocial lobby’) can make a diagnosis of CFS in the complete absence of these three hallmark symptoms, which just throws the entire body of research literature into the shitter. Because not only is CFS thought to be comprised of different subgroups in itself, but you have a whole another group of patients who have been diagnosed as CFS but who really have anxiety disorders and/or depression being mixed in. That is not to say that anxiety disorders and/or depression aren’t real, but rather that they are distinct from CFS.

    Add to this the UK’s 1991 ‘Oxford’ criteria for ‘CFS’, which only requires fatigue and no other symptoms (I think fatigue made worse with exertion to be specific) and which is only used by psychiatrists and psychologists in the UK and the Netherlands who believe CFS to be a classical behavorial disorder, and you get an even huger clusterf(*^ taking place. According to patient advocate Mary Schweitzer, the Oxford criteria were published as a direct counter-argument against the Holmes definition of 1988 which defined “chronic fatigue syndrome” in the first place. Unlike Holmes, the Oxford definition permitted NO physical symptoms, and included major melancholic depression.

    Cluster.

    F*^$.

    PS- Now the CDC, in an attempt to cover up their epic incompetance of the past several decades, is going to say that anyone with the retrovirus doesn’t have CFS to begin with. All I can say is this- “Fasten your seatbelts, it’s going to be a bumpy ride!”

  • John

    The antiretroviral thing is tricky- HTLV causes significant disease in infected individuals yet antiretrovirals don’t cure tropical spastic paraparesis, with HTLV seeming like a better analogy to putative XMRV/MLV-related disease than the more commonly used HIV scenario.

    Also at the recent XMRV Workshop in the webcast Q&A, which is set to be archived in a couple days, it was mentioned that within the past couple weeks they found a potentially significant difference in results with different methods of sample preparation, so fingers crossed it could get worked out fairly quickly as to what has caused the discrepancies reported thus far.

    And they’ve looked for XMRV in several different diseases/populations, but all have been zero-zero similar to the negative CFS/prostate cancer studies.

    Would the 100% glyco-gag match not indicate lab contamination of samples? What does that mean?

    Thanks for the great podcast!

  • guest

    im XMRV positive, im scared.

  • http://pulse.yahoo.com/_KHLTRE4EXDP4ZTYCFPKP5SPEPA Elle

    It depends also on what is meant by “follow-up.”

    If this is referring to logistics, researchers should consider doing home visits and blood draws on subjects who are too ill to make it into a clinic or hospital. As someone who has done medical home visits, I am aware there are many lab and imaging tests (including X-rays and ultrasound) which are able to be done in the home setting which could not be done in the past. Of course, if we are talking about things like CT scans, then the answers might be no.

    Nancy Klimas at the U of Miami is doing a study which involves home visits. If researchers were truly interested, they could be more creative and come up with such solutions.

    I agree with the point about “active placebos” made by LC. A majority of non-CFS clinical studies looking at medications do not use “active placebos.” Besides which, neither investigators nor CFS subjects know what to expect anyway with antiretrovirals so it’s not like CFS subjects can search the internet and can tell whether they are on placebo or not. I don’t understand this particular point.

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  • lancelot

    Several studies have not found XMRV in HIV patients. We all know how many opportunistic pathogens HIV/AIDS “picks up” such as HHV 1-7 reactivation which is also seen in ME/CFS.