Experiments In Vivo

So here we are, two years after the scientific community was told which rock to look under, still arguing about whether two or three scientists can reproduce their work or not. In the meantime, a promising avenue of treatment, antiretrovirals, has been shut down like a prohibition, for the flimsiest of reasons. Too dangerous (compared to what?). Too expensive (for whom?). AIDS patients need their drugs (since they have a serious illness). How can we treat it if we don’t know the precise agent we are treating? The way doctors treat people every day. Best guess. I actually think we have a better model than the rheumatologists are using to prescribe incredibly toxic drugs for patients with autoimmune diseases.

AIDS patients have to be treated forever, but we don’t have any idea if that is true for us or not. Just think how much we’d know now if part of the money that was spent trying to find a virus that doesn’t exist in nature could have been spent on very simple clinical trials of safe, existing drugs. It is becoming clear that at least some are concerned about lab contamination by viruses that are very good at infecting human cells in vitro. See Zhang and Sfanos on the side bar. It’s about time somebody worried. Whatever works, and fear is a good motivator. It worked for HIV.

Here are a few excellent papers that have helped me to refine my working model, though I don’t like it that it is going towards greater complexity, since I like grand unifying theories. But the level of complexity of the problem is intersecting with the state of the art. Cutting edge sequencing and analytics are required.

I still think it’s simple retroviruses at the bottom of it, and maybe not just gammas. Simple retroviruses go for the germ line and become endogenous. Multiple assaults. Most end as ineffective sequences, with deletions, tamed by restriction factors that give an individual’s offspring an evolutionary edge. ERV’s can be defective and still cause disease. They can even become symbionts:

Defective sequences can be reconstituted by new incoming. It is not as simple as one sequence or one virus, or even five strains of one virus. Lots of viruses and pieces of viruses. Lots and lots of exposures, if it came from vaccines, grown in all kinds of cells, murine and avian, administered parenterally to most of the human race for decades, and subject to recombination. There were clearly waves when people got sick, but those may have been recombination events, when some necessary piece was supplied to reconstitute something that was there already. Or maybe there were waves of helper viruses that went out and turned on what was there. Or particular environmental toxins that activated one from an earlier invasion (from the Weiss paper above: “..we were able to show that treatment of normal chicken cells with a variety of activating agents such as ionizing radiation or carcinogens stimulated release of virus..”).

This was probably part of the problem too; endless selective breeding of sick mice that produce retroviruses that they are resistant to, but the cells of other species may not be, hence putting lab workers at risk, especially those working directly with tissue culture and xenografts. The Mouse Trap: The dangers of using one lab animal to study every disease. Engber.
The younger women I am seeing, and who have written to me, often have symptoms consistent with PCOS (polycystic ovary syndrome). The few I have tested in my practice, have laboratory evidence of LH insensitivity, LH/FSH ratio greater than 2 in a menstruating woman with normal FSH. LH insensitivity interferes with the egg being released from the developing follicular cyst, so the corpus luteum doesn’t form properly, progesterone isn’t made normally, and estrogen dominance, with all its problems, ensues. The condition is also characterized by high androgens and a dysmetabolic syndrome causing central body fat distribution. Does progesterone deficiency favor the virus? Physiologic replacement is a powerful therapeutic option for women so affected. PCOS is a very common cause of reduced fertility, so if germline retroviral infection is involved, it isn’t a very good strategy for a virus that is not spread horizontally. However from an evolutionary perspective, if the virus succeeds in most of its hosts, the few that become infertile and are a dead end, are just part of the evolutionary process. Remember that only a very small percentage of HTLV patients ever get sick and genetic factors are probably key.
Env proteins are strongly implicated in the neuropathogenicity of MLV’s, and also recognized in the evolving retroviral model of RRMS (relapsing remitting multiple sclerosis).

Could antiretroviral drugs be effective in multiple sclerosis? A case report. Maruszak: This is a letter to the editor behind a paywall, but documents the resolution of significant neurologic impairments, including bladder and bowel incontinence, in an MS patient after being treated with HAART for HIV infection. The patient developed MS and was infected with HIV in ’85. He was treated with HAART in ’96, improved rapidly with resolution of many MS symptoms, including fatigue, within two years. It happened in the late ’90’s and it was just published… It is the only paper I could find where anyone has documented an effect of arv’s on MS, despite the fact a retrovirus has been suspected for over a decade. How’s that for blinders! What is it about this particular class of drugs that has everybody so spooked? Is it because AIDS patients have to take them forever? It may not be the case here. The best anecdote I’ve heard was 16, only sick for 8 months, responded quickly, stopped treatment after 6 months and has stayed well, as far as I know. And even if the drugs are for good, they are very clean drugs. HIV infected people have gotten very good research into their disease.

The literature suggests that the search for a sensitive enough reverse transcriptase assay was abandoned for HIV, as specific testing became highly sensitive. However, if you were looking for generic replication competent retroviruses that you could monitor, a clinically useful RT assay would seem to be indispensable. RT assays have been used in the lab since the late ’60’s, but seem to have been abandoned more recently, except for research purposes involving monitoring of retroviral vectors. Maybe one of the scientists reading can explain why this test isn’t clinically available? Why wouldn’t it be useful for MS, for example, given the suggestions of the papers above concerning that disease? Maybe some money to be made here, for any diagnostic test patent seekers who might be reading.

Ali remains on Viread/Isentress and continues to be surprised by greater than expected resilience, e.g. rapidly recovering from having her wisdom teeth extracted. I came off Isentress a couple of months ago and didn’t notice much of anything. It didn’t seem a good idea to stay on monotherapy and someone already committed to the experiment needs to give a protease inhibitor a try; therefore, I started Lexiva two weeks ago.

There was a recent paper showing that amprenavir inhibits XMRV in vitro (Li/Wlodawer on the side bar), but also, there are several clues in the literature that suggest that it might inhibit MLV proteases more broadly. HIV treatment wasn’t truly effective until PI’s were added. The first time I tried Lexiva, as a fourth drug then, still using an HIV model of HAART, it had the unexpected effect of CNS activation and it is doing that again. I describe it as “turning up the volume”, a perceptual shift. I am more reactive, but that is dying down now. It doesn’t do this with AIDS patients and I have no explanation, other than it moves the disease in some way, since I don’t see how it is an adverse effect of the drug. The other arv’s shook things up for me for a while too, but that felt like an inflammatory flare of usual symptoms. Physically, I think I feel a bit better, stronger in the last few days, but it could well be the swing of the pendulum. I will stay the course and report.

Here is a letter that I received a few days ago:

Dr. Deckoff-Jones,
I’m writing to you in the hope that by sharing a little of my medical history I can help. If XMRV is totally out of the picture it must in my case be a related retro-virus. I think if there were a place to pool ME/CFS patient information there might be something made obvious through comparative analysis.
I started on AZT about a year and a half ago On 3/6/10, my health seemed to gradually improve, by december I developed pain on the inside of both legs so at the end of december I stopped taking AZT. I declined rapidly and by the first of February I was worse than before I started on AZT. A few days into February I started taking Viread and Isentress and felt even worse for the next 10 days to two weeks (which I had read to expect this) I actually kept busy just to take my mind off how bad I felt.
Gradually I started to feel better and by the end of May of this year I thought I was well on my way to a normal existence. I think it was July and September I declined. Today I am definitely better than when I started but still far from my goal. I don’t want to stop taking anti-retrovirals.
I’m wondering if I would have done better if I had included Emtricitabine and if I should start now. I will discuss it with my doctor. If a yet unknown retrovirus is the culprit, it’s anybody’s guess as to which drugs are most effective.
I think the best course of action would be to find the cohort who have responded to the three above mentioned drugs and divide them into groups to see how they respond to other (additional) anti-retrovirals.
I think everyone affected would be perfectly okay with finding the treatment before finding the cause. Even if it’s a small subset of patients, we will have chipped away a little at this stumbling block we call ME/CFS.
I have had this for 18 and 1/2 years and I’m about to turn 64. So like everyone else I want answers now.

Sick patients trying to figure it out on their own, the ultimate failure of an ineffectual system. Scientists not only don’t talk to patients or doctors, they don’t even talk to each other, since somebody might steal their ideas. All closeted, each guy alone in a lab looking at a little piece of the elephant, writing in notebooks with pens?!! No copies? It seems even more dysfunctional than our broken medical system, that a dispute between a scientist and their employer can result in the hopes of an entire patient community being dashed on the shoals of intellectual property law and the criminal justice system.

I would like to thank Dr. Lipkin for being the voice of reason in an insane situation. He is positioned to help us. I hope he stays interested in our plight. We have very few friends, but maybe one new one who has the wherewithall to crack the case.

I maintain a confidential elist for patients taking antiretrovirals. Anyone reading who is taking arv’s and who would like to be signed up, please contact me: jdeckoffjones@gmail.com

Today’s song: If Not Now
by Tracy Chapman
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210 thoughts on “Experiments In Vivo

  1. >"In retrospect, I say I did the disease a disservice. I might have done the patients a disservice, and I might have done the field a disservice."
    – Elaine DeFreitas (page 682 "Osler's Web"

    The context of this is that DeFreitas felt badly that she had not been able to push further in hunting down the retrovirus she found in CFS patients. She also discussed at length the work of a scientist, Dr. Panem who found a retrovirus in lupus patients.

    So now it appears that Alter and Lo are wimping out on the world. Where are the heroes?

    Keep focused, patients. Remember that in 1950 we hardly heard of lupus or MS, certainly not CFS or fibromyalgia or ALS. Something has spread through the human race since the 1970s and it ain't good. Will there be any scientists with the guts to keep searching?

    Maybe we can talk big pharma into doing the research. How about LaRoche for testing and Gilead for treatment? They stand to gain even if they don't give a rip about us.

  2. >@anon

    "Kuppeveld never showed his assays could detect positives."

    From the Van Kuppeveld letter to Annette Whittemore (http://www.umcn.nl/Research/Departments/kcv/Documents/F%20v%20Kuppeveld%20brief%20naar%20Whittemore.pdf):

    "Since our findings were based on solid, sensitive PCRs (described in detail in our paper) that efficiently detected XMRV in a cell line, as well as in positive samples that were provided to us by Dr. Judy Mikovits,.."

    So yes, Van Kuppenveld did demonstrate that his assays could detect "clinical" positives that were sent to him by Mikovits. He didn't put it in the actual paper, but since you're apparently perfectly content with evidence from letters and internet articles, I guess this will probably do too.

    I guess your agenda is to be seen by vulnerable sick patients as some kind of authority to cling to. Unfortunately, you must do that by providing a non-mainstream viewpoint by default – only this can make you special as one of the select few that know and understand "the truth". What I find incredible is your apparent ability to totally disregard facts in this process.

  3. >Paula you are right, but those companies rely on NIH funding and FDA approvals. It is true the viruses cannot be denied forever, so I suspect they are hoping for neclear war.

    RRM/Mark G go home. Kuppeveld goes on to make it clear who and where he is talking about samples being tested. If they had used the assays in their paper to test they would have reported the results of those clinical positives in the paper, they didn't.

    "Of note, the samples that you found positive were repeatedly negative upon retesting in our lab"

  4. >@Anon

    "Of note, the samples that you found positive were repeatedly negative upon retesting in our lab"

    If you are serious, you are serously losing it.

    Here Van Kuppeveld is clearly not talking about the positives he received from Mikovits. He is talking about the samples FROM THEIR STUDY THAT HE SENT to Mikovits, that she found positve. Those samples were and remained negative upon retesting in their lab.

    Van Kuppeveld clearly and unequivocally says in that letter that he detected XMRV in the positive samples that were sent to him by Mikovits. Like I said before, I am amazed how you can totally disregard this and quote a totally unrelated part of the letter in "support" of your position.

  5. >Van Kuppelved did not publish any data on having used clinical positives to validate the assays he used in the paper.

  6. >""Anonymous said…
    Science did not retract because of AZA, which they asked to be removed from the label for publication. The study was blinded. The gel in the paper was one of dozens. Others were treated.

    December 22, 2011 2:00 PM""

    Can you please elaborate on this? What is your source(s), pls?

    To the person who thinks they would have found a virus by now if one had been involved, I really hope you were kidding…

    re XMRV and HGRVs:
    I still think nothing has been settled conclusively. With Silverman retracting his flawed detection of XMRV, I'd say there is some, but not a lot of evidence for HGRVs in ME. That there is a lot of circumstantial evidence that XMRV proper and very circumstantial evidence that perhaps HGRVs are not associated with ME, but far from conclusive. Dr. DJ is far more educated on these things than I or most posters here are, so I tend to give her opinions weight.

    @Tony Mach, pls tone your yelling and insults down. Dr. DJ is very far from a quack. As she says, she wants and has been pushing for formal studies on ARVs in ME for a long time now! In the absence of that (because of bias and persecution) she is collecting the best evidence she can; I laud her for this and think it may be very valuable.

    Tenofovir is given to HIV negative people in large studies by CDC in Africa and San Francisco for years now and all news articles on this talk about how great this is and not a word of caution, that maybe HIV negative healthy people should not take ARVs. There is a huge bias against bona fide ME science and patients.

    Please attack the real villians- Wessely, CDC, NIH, etc. I am beginning to suspect you are not actually an actual ME patient based on your attacks.

  7. >@Justin

    You have heard this already Justin and I am questionning who you are.

    The blot in the paper is one of many. As the study was blinded and due to them not knowing how these viruses act they had to run many different experiments. Coffin saw the original gels and labels and approved for publication. However to fit that into a publication it was all reduced to one blot and the labels were altered as requested by Science to protect patients identities and to simplify. There are records of patients discussing the use of AZA in the paper from two years ago. Science and Coffin knew it was, as does anyone who should know that is what you must do to reactivate a latent retrovirus. Science accepted the paper knowing AZA was now not mentioned, but two years later they forget?

  8. >"Where are the heroes?"

    I don't think we begin to know how many there are. Many more than we realize, trying to stay under the govcorp radar so they're able to continue the work with meager, pathetic budgets.

    It's possible that everyone on the International Consensus Panel is a hero as well as the editor of the Journal of Internal Medicine for printing the International Consensus Criteria in October. I say this because it had to be risky for them.

    And you can't talk about heroes without mentioning Judy Mikovits…

    Last summer I stumbled on a utube. If I can find it again (or if anyone else can), the link will be forthcoming.

    In the utube, Judy states (possibly right after joining the WPI) that collegues had warned her that if she got involved in CFS it would be a "career ender".

    So…she knew. She knew and was still willing to do the right thing. Willing to fall on a sword for all of us.

  9. >Wow – I can't believe the personal attacks on me! I'm simply a very very sick patient – "People are dying and suffering, you have no interested in helping them."

    Mary Schweitzer had great results with Ampligen as long as she stayed on it. I was merely sharing my experiences with what I think is a pretty dangerous drug and the results that *I* saw in my group. Underwhelming to be sure. If you can drive, shop, cook, clean, socialize, why in the world would you need a drug anyway? What motivates doctors to put patients in studies who don't really qualify? Doesn't this skew data? And FWIW… despite the severity of my illness I certainly have helped many, many by befriending them, holding their hand, yes, even sending some desperate pts $$. This is one very werid discussion and skewed in only one direction. Outta here…!!

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