Whether or not the retrovirus XMRV is a human pathogen has been debated since the virus was first described in 2006. The answer is now clear: the results of Blood XMRV Scientific Research Group, along with a partial retraction of the 2009 Science paper describing identification of the retrovirus in patients with chronic fatigue syndrome (CFS) show that detection of XMRV in patient samples is a result of contamination.
The Blood XMRV group obtained new blood samples from 15 individuals previously shown to be positive for XMRV (Lombardi et al., 2009) or MLV (Lo et al., 2010) ; 14 of these were from CFS patients. Fifteen blood samples were also obtained from healthy donors. The samples were coded and sent to 9 laboratories for analysis. These laboratories (Abbott Molecular, Abbott Diagnostics, CDC, FDA/Lo, FDA/Hewlett, Gen-Probe, NCI/DRP, and WPI) conducted validated assays for viral nucleic acid, viral replication, or viral antibodies. Positive control samples were also included that were ‘spiked’ with XMRV, in the form of cell culture fluids from the cell line 22Rv1. Each laboratory was at liberty to choose which assays to carry out.
Two laboratories reported evidence of XMRV in the coded samples. Only WPI identified positive specimens by PCR: two from negative controls, and one from a CFS patient. The FDA/Lo laboratory did not detect any positives by PCR, using the same nested assay that they had previously reported in their published study. The samples tested included 5 specimens that were positive in the Lo et al. study.
Lombardi and colleagues have previously concluded that viral culture is the most sensitive method for detecting XMRV; however the FDA/Hewlett laboratory failed to culture virus from CFS samples. This laboratory did culture virus from positive control specimens, demonstrating the sensitivity of their methods. The FDA/Ruscetti laboratory recovered virus from 3/15 CFS samples but also from 6/15 negative control specimens. WPI did not carry out viral culture assays due to contamination of their cell lines with mycoplasma.
Four laboratories tested the samples for the presence of antibodies that react with XMRV proteins. Only WPI and NCI/Ruscetti detected reactive antibodies, both in CFS specimens and negative controls. There was no statistically significant difference in the rates of positivity between the positive and negative controls, nor in the identity of the positive samples between the two laboratories.
These results demonstrate that XMRV or antibodies to the virus are not present in clinical specimens. Detection of XMRV nucleic acid by WPI is likely a consequence of contamination. The positive serology reported by WPI and NCI/Ruscetti laboratories remained unexplained, but are most likely the result of the presence of cross-reactive epitopes. The authors of the study conclude that ‘routine blood screening for XMRV/P-MLV is not warranted at this time’.
One of the authors on Lombardi et al., Robert Silverman, decided to reexamine some of the DNA preparations from CFS patients that were originally used to detect XMRV DNA by PCR. He found that all the positive specimens from CFS patients were contaminated with XMRV plasmid DNA. Therefore the authors of the original study have retracted Figure 1 (single-round PCR detection of XMRV in CFS PBMC DNA); table S1, XMRV sequences, and figure S2, phylogenetic analysis of XMRV sequences.
A puzzling aspect of Silverman’s results is that XMRV plasmid DNA was detected only in samples from CFS patients, not healthy controls. This pattern would not be expected if the specimens were properly blinded, that is, coded so that the investigators did not know which were controls and which were from CFS patients. The authors offer no explanation of these findings.
The paper reporting contamination of samples with XMRV is entitled ‘Partial Retraction‘. It’s not clear to me why the entire paper has not been retracted. After removing the PCR and nucleic acid sequencing results, there is no evidence indicating the presence of XMRV in the patient samples. The remaining experiments show detection of a retrovirus by cell culture experiments, and the presence of viral proteins or antibodies to the virus in clinical specimens. None of these findings prove that what is being studied is XMRV. The title of the original paper ‘Detection of an infectious retrovirus’, XMRV, in blood cells of patients with chronic fatigue syndrome‘, is unsupported.
In an accompanying article on the XMRV story entitled ‘False Positive‘, Judy Mikovits of WPI notes that “Anyone who says this is a lab contaminant has drawn the wrong conclusion and has done a disservice to the public”. She goes on to imply that a gammaretrovirus is likely involved in CFS. On the contrary, pursuing the CFS-gammaretrovirus hypothesis is a disservice to those with CFS, and detracts from efforts to solve the disease. There are no data to support such an association, and to suggest that a lab contaminant, XMRV, has pointed the way to a bona fide etiologic agent seems implausible.
XMRV does not cause CFS. The virus arose in mice between 1993-96, and its detection in patient samples is clearly a result of contamination. Reaching these conclusions has required a long and often contentious journey that has highlighted the best and worst aspects of scientific research. There are many lessons to be learned from XMRV, but an important one is that science progresses not from the work of a single investigator, but from the collective efforts of many laboratories. XMRV reminds us to trust science, not scientists.
If the data were actually peer reviewed you might have a point.Â
If you don’t opt for peer review, you really should disclose this information. Otherwise the data just cannot and will not be trusted.Â
I will say it again as you missed the point entirely. Â
This is shear ignorance of the peer review process.
Good to see you’re questioning your own credentials. 😉
Great, vouching.
Finally we can do away with the peer review process and let vouching about unpublished data take over.
– Yes I am really desperate by the ever growing evidence against my beliefs. Very soon the politics will be over, I am sure.
– Hanson reported this at the recent conference. Sorry, but the bad guys probably “got to her” too.
– The problem is that there is no “wild virus”.
– Please check Figure 2 of the Lo paper. Same assay. Positives detected.
– Yes. Ruscetti did, as well as Bagni.
– WPI did complete culture by culturing some nice mycoplasmas.
– I mean that Mikovits was well aware of the (supposed) VP62 problem. She stated over a year ago that relying on VP62 was the reason for the negative studies, and that WPI was not calibrating their assays to VP62. However, because of the Silverman finding and gullible people, now she suddenly thinks her disastrous results are the consequence of…relying too much on VP62. Yeah, makes perfect sense. Really, this virus is just pining for the fjords….
I am hardly fond of replying to myself, but in the interests of trusting science, I think this is worth reporting.
http://www.nature.com/nrendo/journal/vaop/ncurrent/full/nrendo.2011.153.html
It’s all there–or at least a good dollup of it. Inactivity, depression, stress. Antidepressants and Cognitive Behavioral Therapy. Well done. The scientific method at work.
As was seen on Science-Based Medicine two years ago…why would anyone look for a virus in CFS anyway?
Now, since so many loud voices project them so loudly to proclaim that all these patients really need is to pick themselves up off their couches and/or take proactive steps to deal with their depression…I can’t see any reason why people dealing with a condition that Nature reports today is related to stress shouldn’t do their civic duty (if they can’t/won’t/are too lazy to do anything like, you know, actually go to a job just like the rest of society; it’s not like this is a legitimate disability, or anything). And…
Well, I won’t go there. It’s as pointless as the useless arguments going on above. Feel free to continue to ignore my posts. None of this is really all that important, anyway. It’s only stress, after all.
What is wrong with you? Â How about I take you through this. Â Please describe the peer review process as you imagine it to be? Â
Are you questioning the honesty of Frank Ruscetti?
HGRVs will be accepted as associated with ME/CFS. That is wild virus. There is no doubt regarding that.
Hanson has not reported her results of finding HGRVs are contamination. You a lying.
It is not Lo’s positive assay, you are lying again.
Ruscetti never checked the Lo samples and Bagni has never shown her assay to be diagnostically validated. Only using a clone not found in nature.
The WPI were not allowed to complete the culture. What do you say that is not a lie.
Mikovits stated that VP62 is not enough because it would never be integrated as a wild type virus would. Singh said the same, but failed to follow her own recommendation. The WPI and NCI never used and have never had VP62.
Okay. From the back of my head.
You submit your paper to the journal. The journal’s editor(s), which are not scientific peers (at least, not necessarily) check(s) if it is an interesting study. If not, the paper gets rejected right away. If it is interesting, the the manuscript will be sent to a couple (two, sometimes three) peer reviewers. These peer reviewers check the data, check the conclusions, and check whether the data support the conclusions. They then either advise the editor(s) to accept the paper, reject it, or advise additional data/experiments. Of course, if anything is unclear, they will ask for additional information (usually through the editor(s)). The editor(s) decide(s) on the basis of the peer reviewers’ advice and communicate(s) the decision to the authors. If the peer reviewer(s) request(s) additional data/experiments and the editor(s) follow(s) this advice, the amended paper of course gets re-submitted to the peer reviewers.Of course, this is a general explanation and (e.g.) does not apply to PNAS track 1 papers (like Lo et al.).Now, if I were peer reviewing Judy Mikovits’ latest finding regarding VP62 contamination, I’d demand that the name of the independent lab would be disclosed to me (or, at the very least, the investigators involved). If Mikovits would not be willing to share this information with me, I would advise to either:a) reject the paperb) demand an extra experiment at an independent lab that isn’t as shy as this independent labNow, please explain to me what is wrong with me. I wanna know, you know?
http://www.youtube.com/watch?v=n3kdU5FhH2U
Go to 14:45. Mikovits confirms that the NCI/Ruscetti lab isolated virus as well as detected an immune response from the very same Lo patients that were in the BWG study.
– Hanson has reported her PCR results are due to contamination. This was reported by several sources that saw her most recent presentation (09/23).Â
– Please check Figure 2 of the Lo paper and EXPLAIN to me what was different.
– “WPI never used VP62”. Exactly. This is why it is a poor excuse to say that you’ve relied a bit too much on the Silverman VP62 findings.
So what is it that you don’t understand?
I am glad you agree with my explanation.
I will say it again as you missed the point entirely.
If Mikovits had actually submitted her data for peer review you might have a point, but she didn’t.
No. I am all for the vouching process to take over the peer review process.
“Busch must be devastate.”
You misspelled Mikovits
Honesty and integrity are an integral part of the peer review process. Â So don’t question the honesty of Frank Ruscetti or Judy Mikovits.
Work can be presented around conferences for years before publication. Â This is irrelevant to the peer review process. Â Again, you are questioning the honesty of Frank Ruscetti and Judy Mikovits. Â What is you issue.
You previous comments and the explanation do not interact.Â
Of course the problem is that the article Jack quoted from, is also in the “public domain”.Â
While you are saying that Jack is incorrect, you fail so substantiate this assertion with a quote from the “public domain”. Â Where is this data that shows this assertion is incorrect? Why have the WPI not responded to this apparently incorrect and damaging quote?
The way I see it, the “public domain” shows that Silverman has sent VP62 to WPI. Of course, I am perfectly able to stand corrected if provided with evidence to the contrary.
Yes, work is presented around conferences. The idea is to get some support for your views, as it may help you to publicize your results in a peer reviewed journal.
However, until this moment, I had never heard of a scientist who turned down a prominent peer reviewed journal in order for her to reveal her findings at some conference.
“No, Science, no Nature, no Lancet, I really don’t want this in your journal, I only want to show this information at conferences. It’s really more reliable, you know.” Amidoingitright?
It really works both ways, so I take it you don’t question the honesty/integrity of:
McClure
Wessely
Singh
Coffin
Van Kuppenveld
Van der Meer
Switzer
Patkak
Paprotka
Groom
Levy
Shin
Knox
Hohn
Silverman
Stoye
Or do you?
Actually my comment was about the effect of lack of Trizol on the integrity of the virus or the cells. What you fail to understand is that detecting retrovirus by itself is not enough, you need to show that the virus integrated in the genome, it is an essential part of the replication cycle. Even if the cells that they sent were destroyed you should still be able to detect provirus that is integrated into the genome of the cell. BTW I never heard of Trizol being used as a preservative for retrovirus transport. I’ve never used anything like that in any viral transports, my viruses were never degraded after the transport.
NCI/DRP performed the PCRs, not Ruscetti. But you said NCI performed no PCR in the original comment, that’s why I made that comment.
“The virus found in people with ME is not VP62.”
Is that why all the WPI submitted sequences that were from viruses isolated from patients are almost exactly VP62?
“Why would you imagine that assays diagnostically validated to a virus
that is not VP62 would detect an imaginary clone they were not designed
to detect. ”
WPI did their own assay in this study nobody designed their assay for them. How do you explain their detection of the virus in the negative controls?
@Bullybeef
The CFSÂ samples that left WPI were contaminated with VP62 pasmid prior to Silvermann lab receiving them in 2009. Lombardi paper states all of these ABs detected the human VP62 XMRV strain grown in human Raji, LNCaP, Sup-T1 cells (fig. S3)(5).
@001ef4f3782d7ada4d8b76d6b84f9117:disqusÂ
Who are all these people that speak for the WPI and Mikovtis? What gives them the right to contradict the WPI and Mikovits own statments?
WPI Site states:The spectrum of neuro-immune diseases including: Myalgic Encephalomyelitis (ME/CFS), Atypical MS, Fibromyalgia and Gulf War Syndrome, share common abnormalities in the innate immune response, which result in chronic immune activation and immune deficiency.
We have detected the retroviral infection XMRV in greater than 95% of the more than 200 ME/CFS, Fibromylagia, Atypical MS patients tested. The current working hypothesis is that XMRV infection of B, T, NK and other cells of the innate immune response causes chronic inflammation and immune deficiency resulting in an inability to mount an effective immune response to opportunistic infections
Mikovits continued to strike a defiant tone, insisting that XMRV had not been ruled out as a potential cause of CFS.
“Anyone who says this is a lab contaminant has drawn the wrong conclusion and has done a disservice to the public,” she told the journal.
She vowed to continue working to prove that XMRV is a genuine virus and is present in CFS patients. “The virus is real,” she told Science. “I have isolated it from patients. I know it’s there.””The conclusion of the Blood Working Group was that we don’t have a reproducible assay to detect XMRVs in the blood — not that they weren’t in the patients at all.”
She vowed to continue working to prove that XMRV is a genuine virus and is present in CFS patients. “The virus is real,” she told Science. “I have isolated it from patients. I know it’sars an outbreak of XMRV.
There is no research data or paper to date that proves HGRV causes ME. To state otherwise is sheer lunancy!
These statements are pure delusional at best. It even contradicts WPI and Mikovits
Were you in Silvermann lab standing behind him or something?
Nope!
What Lab? Name the Lab?
The posted link
http://treatingxmrv.blogspot.com/2011/09/when-going-gets-tough.html#comments.
shows some slide of JM and I was directly stuck with slide no. 3 ’cause I saw this IP plot already in 2010 on JM poster in Prague at the “Centennial Retrovirus Meeting”.
But, of course just a “small mistake” 😉 at 2010 the third lane is inscribed with a different sample/patient number.
A mistake here, a mistake there (single round PCR vs. nested PCR) makes up a fine Science pubilcation.
Btw., what a massive plasma virus load! Guess this is hard to reach even within chronical infected HIV patients and for sure never in HTLV infected individuals.
Even if, Dr. Racaniello, it is as you pronounce it to be the case-there are serious problems to be addressed as to liability for these HGRVs/XMRVs to be floating around in all sorts of places-kits, mixing supplies for  reagents, vaccines if we have contamination issues with VP62.  Â
However, the Blood Working Group’s goal was to test the blood supply as it is presently. Â The results do not state that HGRVs are not in the blood. Â It says that they are levels to low to detect in the samples as they are saved in blood banks. Â This study was not about association of HGRVs/XMRV to disease. Â
WPI continues to do good science, and found and are finding HGRVs. Â They didn’t just find the Silverman VP62 clone. Â Notably, there are several sequences in the Gen Bank archives now, and not merely from WPI. Â
There are some very excellent papers out there exploring disease implications for HGRVs/XMRV further.  The whole world of research laboratories and medical schools cannot possibly be merely “contaminated” with this stuff.  There are good papers (I read them) from far before 1993 which in hindsight address some of the base issues involved with HGRVs.  Please see the mecfsforums.com.  There is some good basic research going on, and I find premature to dismiss things out of hand.  Nothing is that black and white-especially the HGRV/XMRV issues.  There is an issue with the VP62 clone which now has been dealt with.  The science yet stands in favor of a problem with HGRVs-what creature has been traveling with humans across the aeons but the field mouse?
http://blog.cleveland.com/metro/2011/09/cleveland_clinic_researchers_r.html
“The source of the contamination is not known, but Clinic officials say it occurred OUTSIDE their labs”
Where’s your integrity?
That is for work not part of the BWG. So they never went near them.
Hanson has said no such thing. Stop lying.
Primers in Lo
The Lombardi team never relied on Silverman contribution. The paper by itself supports that HGRV are present. Confirmed by Lo too. VP62 is not about HGRVs. All the evidence is against this.
Clinic officials, not Silverman.
Where is your integrity. Â
The nuttiness of the response to the evidence against XMRV being related to CFS is really damaging to CFS patients. There are lots of legitimate complaints to be made about the way CFS has been treated by researchers over the last two decades, by these reasonable concerns are now likely to be lumped together with the conspiratorial rantings of a handful of patients unable to believe that the WPI were wrong.
Following the poor results from PACE and the way they had to be spun to the media, and the increased interest that from a wide range of researchers that XMRV had broughtto the problems of CFS, it looked like we were in a position to start making some real progress. Unfortunately, it seems that there are a handful of patients desperate to pull defeat from the jaws of victory.
I’m really worried about the impact that just 20 internet posters can have on the way that all CFS patient’s and their concerns are viewed.
One other thing: At this point, I don’t think it’s fair to expect CFS patients to trust science. There are a lot of poorly done CFS studies in journals that have caused real problems for patients (I seem to remember one being discussed in a virology podcast, in which the dangers of researchers unconsciously manipulating statistics to get the results they wanted were mentioned). I expect that this poor history has fed into the more conspiratorial response to the BWG from some patients, and that this in turn will mean that more legitimate complaints about past papers are less likely to be treated seriously.
I cannot yet trust ‘science’ with regards to CFS, but I can still recognise that the evidence is very much against the WPI’s claims.
Please don’t pretend to be a concerned ‘patient’. I’m afraid the following comment gave you away: “Following the poor results from PACE and the way they had to be spun to the media”. Nice try.
Despite, the many blogs, articles and sermons (aka the latest TWiV podcast) published this last week, there are thousands of sufferers, journalists and scientists yet to be convinced. Just a few more than the ’20’ you allude to.
– You said:
“Ruscetti never checked the Lo samples”.
I just proved that to be completely wrong. You are not really accusing me of being a liar by denying that, but Judy Mikovits.
– Re:Hanson.Â
Just see:Â https://twitter.com/#!/CortJohnson/status/117297473415954432
Or:Â https://twitter.com/#!/DeBortgjemte/status/117234073302347776
– Primers in Lo (Simmons et al.):Â 419F/1154R (first round) and GAG-I-F/GAG-I-R (second round)
Primers in FIGURE 2 of Lo et al.:Â 419F/1154R (first round) and GAG-I-F/GAG-I-R (second round)
Same primers.
– And because the Lombardi team never relied on the Silverman contribution, the Silverman retraction is no excuse for NOT FINDING WHATEVER they were finding in Lombardi et al.
Evidence for integration of HGRVs in people with ME is for later research to discover. Â You appear to want the entire family of viruses to meet Koch postulates (as they now stand) within the first positive scientific paper. Â How slow would you like this field to progress.
“Even if the cells that they sent were destroyed you should still be able to detect provirus that is integrated into the genome of the cell. ”
How long did it take scientist to prove HTLV was integrated after Frank Ruscetti discovered the first human retrovirus? Â How long for HIV?
“BTW I never heard of Trizol being used as a preservative for retrovirus transport. I’ve never used anything like that in any viral transports, my viruses were never degraded after the transport.”
I suggest you use pub med. Â Should I be surprised that you are unaware of its use in a specialised filed. Â
Drosha, as the WPI and NCI/Ruscetti are the only labs with diagnostically validated assays, perhaps I took your intelligence to be greater than it is. Â There is no reason to discuss labs with assays only designed to detect a clone.
VP62 does not exist. Â It has never been isolated from a single source. Â An independent lab has confirmed that the WPI and NCI samples do not contain the VP62 plasmid. They are positive for human gammaretroviruses.
There were no negative controls used with the PBMCs and the controls were not screened by all labs.
I don’t question their integrity, I do question the quality of their science. Â Use of clone that does not exist to analytically test the sensitivity of an assay is not diagnostic sensitivity. Â Making no attempt to replicate proven methodology, when theirs fails, is unscientific. Â Â
Levy replicated Silvermans methods and not those of the NCI and the WPI.  Neither the NCI or the WPI were able to detect a HGRV in patient samples testing positive for gag via nested RT-PCR using Silvermans assay.  Levy then used another RT -PCR that could only detect VP-62 because of high stringency primers.  The viruses  detected by the WPI and NCI have nothing to do with VP-62.Â
Do you not agree the Levy paper (Knox et al) should be retracted?
Are you lying again. Â Where is there evidence that anyone has turned down a journal and since when did journals go to scientists asking to publish their paper?
Bit much for you to claim there is a conspiracy.Â
You cannot swap the data for party tricks. Â The viruses were given the wrong name. Â Lo, Alter, Ruscetti and the WPI team have all detected human gammaretroviruses. Â Studies that have been looking for VP62 are not relevant to that research.Â
You would choose to follow journalism that stick with the science, which is exactly what Racaniello set out to say. Â The data is in Lombardi, Lo, Knox, Shin, etc. Â How many studies do you need. Â They all support that there are HGRVs in people with ME and they all support that VP62 is not, even thought that doesn’t exist in nature. Â
You can see it how you like. Â Silverman never sent VP62 to the WPI or NCI/Ruscetti. Â
Ruscetti and the WPI never checked the Lo samples in the BWG, stop lying.
Your best source is twitter!
Clearly you cannot read a scientific paper. Â RRM find another hobby. Â
“or our in-house–designed PCR primer set (first round: 419F/1154R; second round: NP116/NP117) (Fig. 1”
Who didn’t find what Lombardi did? Â Everyone else was looking for VP62, that doesn’t exist. Â The negative papers have also been looking for the same VP62, that again doesn’t exist.Â
small
Here you go (again):
http://retractionwatch.wordpress.com/2011/09/22/why-did-science-partially-retract-the-xmrv-chronic-fatigue-syndrome-paper/
No this evidence proves the samples were not infected when they left the WPI and NCI.Â
http://3.bp.blogspot.com/-LE3KbJjEN2g/TnzsXvAzL0I/AAAAAAAAAEE/Otc07jeQbFs/s1600/Slide07.jpg
http://1.bp.blogspot.com/-pCSELs4zkeM/TnzsYR_SI9I/AAAAAAAAAEI/JpeGZc6kkyQ/s1600/Slide08.jpg
The WPI and NCI/Ruscetti have made it clear their data matches that of Lo, but went further than Lo. Â They detected human gammaretroviruses. Â Silverman gave the viruses the wrong name, now they know why. Â What is the date and source of your quote? Â It is not since this information came to light.
Since there is (currently) no scientific publication that investigates whether VP62 was sent to WPI or not, we’ll have to go by other reliable reports. I note that you have relied on unpublished information several times before.
Yes, this is journalism, but the article got published in the most prominent scientific journal in the world that interviewed the relevant scientists in question before this publication.
However, I am perfectly willing to stand corrected when you provide me with (published or otherwise moree convincing) evidence that says it ain’t so.
No, it wasn’t Mikovits or Bozo the Clown either who said that. It were Clinic officials who said that the contamination occured  OUTSIDE their labs”. Â
Do you seriously consider the possibility that clinic officials are saying this against Silverman’s own opinion? I think that possibility  is arounf 0,0001% – still a FEW MILLIONS time more likely than selecting 11 out of 15 controls to be positive, though, I’ll give you that.
“Racaniello does so much spinning that he should be called professor gyroscope.”
And you are questioning the integrity of other persons with comments like these?Â
– You’re wrong again. Ruscetti checked the samples in 2010 and also checked 5 of those same samples in the BWG. Just because you don’t happen to like the results, is not a good reason to continuously accuse people of lying when they’re actually telling the truth.Â
– Yes, my best source is Twitter, from people who were at the actual conference. Do you have a more reliable source that reported else (of course, from Hanson’s talk at that same conference)?
– “(Fig. 1″Â
My dear Pet101, it is you wo should find another hobby. Multiple times have I referred to FIGURE 2 of the Lo et al. paper. While Figure 1 ALSO shows a primer set that worked, FIGURE 2 shows that the primer set used for the BWG WORKED TOO.
You cannot prove that one assay did not work by showing another assay that did work. I take it that propositional logic wasn’t part of the curriculum?
Are you questioning Frank Ruscetti and Judy Mikovits honesty regarding a lab that is at time does not wish to be named. Â
These slides are not from Lombardi et al. Â So why would you think they should look like those slides?
HTLV viral loads can be considerably higher than those with HGRVs.
ELEVATED PROVIRAL LOADSThe nonmalignant neurologic disorder tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) is accompanied by very high proviral loads, sometimes approaching 1/5 peripheral blood mononuclear cells (PBMCs) (6,9,10). Consequently, substantial proportions of the CD4 T cells in the periphery may be infected. Proviral loads during the long asymptomatic phase of infection are less than in TSP/HAM, although they can be as high as 1/25 PBMCs (11,12). Here is evidence of extensive replication, yet HTLV-I is genetically more stable than any other RNA virus. Another glance at HIV-1 is instructive: HIV proviral loads in latestage disease, AIDS, may get up to 1/100 to 1/30 in the periphery. In other words, HIV-1, too, shows signs of extensive viral replication, although the maximum HIV-1 proviral load is less than that observed for HTLV-I. Yet HIV-1 varies considerably as one would expect (7,8). HTLV-I is clearly the odd man out. How is this possible?http://journals.lww.com/jaids/fulltext/1996/00001/clonal_expansion_of_infected_cells__a_way_of_life.16.aspx