A Reason For Hope

I have something special to share with you, since hope seems in short supply today. One of our own is a clear beacon of light in the fog. Dr. Michael Snyderman’s one man experiment has been presented here before, last in April, clearly showing a prolonged remission of his CLL due to antiretroviral treatment. Since then, he suffered a relapse, while still taking Retrovir (AZT) and Isentress (raltegravir). After carefully documenting the relapse, he added Viread (tenofovir) and here are his stunning results. This is the strongest proof of concept that we have at this time. It is possible he will be ignored, but by all rights, at the end of the day, he should be credited with changing medical history. He has been very brave and very restrained, having done nothing else for his cancer or his CFS, except for antiretrovirals. His leukemia allows for very precise monitoring, but do not forget that he had ME/CFS for many years prior to CLL, and he has experienced clinical improvement of those symptoms as well. It is a game changer, or should be.

click to enlarge

click to enlarge

click to enlarge
The parameters are:
  1. ALC. Total lymphocyte count. White blood cell counts (WBC) were determined on a LH 750 Coulter Analyzer. The percentage of lymphocytes was determined with a 200 cell manual differential and the absolute lymphocyte count was determined by multiplication by the WBC. 
  2. CD-19. Total B-cell count. CD19 percentages were determined by flow cytometry and the total count was measured directly.
  3. Trisomy-12 count. Trisomy 12 is a subclone of Dr. Snyderman’s CLL and probably the most aggressive of the CLL clones. The fact that it is also going down is very supportive of the importance of the response. Trisomy 12 percentages were determined by FISH on peripheral blood mononuclear cells and the absolute count was determined by multiplying by the ALC.
  4. γδ (gamma delta) T-cells. This isn’t a cell count, but a quantitative measure of T-cell clonality based on a PCR which detects gene rearrangement.
  5. ZAP 70. Zeta chain associated protein 70, a tyrosine kinase normally expressed by NK and T cells, is required for normal T cell receptor signaling. ZAP 70 is not normally expressed in B lymphocytes, but has been found in a subset of patients with CLL and appears to correlate with survival. Despite the uncertainty concerning normal threshold values, increased levels of ZAP-70 detected by flow cytometry denote a poor prognosis.

From Dr. Snyderman:

The 2nd graph is designed to make just one point. It shows the kinetics of the T-cells compared to the kinetics of the CLL. The importance is enormous. The gamma delta T-cells have never been tracked before. This shows that they can proliferate, not just remain static, but proliferate autonomously, like a neoplasm, albiet a low grade neoplasm.

At least in my case, the clonal gamma delta T- cells cannot be reactive as my plasma is negative for infectious virus; there is nothing there to react against. I hypothesize that rather than just being reactive, the T-cells contain integrated virus and the virus is coding for viral proteins that stimulate cell division and release of cytokines. Because the gamma delta T-cells tend to increase, cytokine levels must be increasing which at least partially explains why CFS patients get sicker and sicker.  Because the cytokines can stimulate cancer, increasing levels of cytokines is one explanation why cancer gets started and then gets worse and worse. Dr. Mikovits is repeating my cytokine signature to prove that the cytokines are back up again.
It looks as though the growth of clonal gamma delta T-cells which are known to make cytokines, coincident with relapse, may have stimulated my leukemia cells to increase. Cytokines are believed to be able to stimulate cancer. This is relevant to CFS because elevated proinflammatory cytokines are part of the reason that CFS patients get sick. Dr. Mikovits said that at the time of my relapse the DERSE cell assay was still negative for infectious virus so the relapse can’t be blamed on viral resistance. It probably represents the clonal gamma delta T-cells being more sensitive to whatever RT leaked through, despite the AZT, and the tenofovir must be able to shut this down. So Gag and Env must not yet be important to my T-cells. When I relapse again, I will test whether Gag and Env have become important, by adding fosamprenavir, which has been shown to inhibit MLV protease. The data suggests that tenofovir is synergistic with AZT and it may be worth considering using the two drugs together in the future to treat XMLV related disorders. Of course this is a one-person study, but as there is nothing unusual about me, it is a rational starting point for further investigation.
The greatly increased risk for B-cell malignancy in CFS may be due to infection of the B-cell line by XMRV’s. Retroviruses have been thought to cause cancer by insertional mutagenisis. This mechanism requires that the retrovirus proviral DNA be integrated into host cell DNA next to a proto-oncogene thereby inducing activation of the proto-oncogene. A more important mechanism with XMRV’s may be the ability of viral proteins to change host cell gene expression. 
Twenty-four to forty-eight hours after a permissive cell line is infected with XMRV, multiple cellular genes are expressed: “10 genes are implicated in cell morphology, 11 genes in cellular development, 12 genes in cell-to-cell signaling and interaction, 11 genes in cellular movement and 13 genes in cellular growth and proliferation” [1]. Spadafaro has shown that reverse transcriptase can cause gene activation and lead to the malignant phenotype [2]. In some retrovirus linked cancers, env [3] and gag [4] may also be important in malignant transformation. 
The finding that a retrovirus did not cause malignant transformation de novo in tissue culture would be irrelevant to the clinical reality of human cancer. It is accepted that multiple events are necessary to convert a cell line into a pre-neoplasm or a clinically important neoplasm. Human cancers have mutated genes and changes in gene expression that could make them permissive to infection by retroviruses. The retroviruses could induce further changes in gene expression that would make the infected cell line behave in a more malignant fashion. The corollary to this is that treatment that would subtract viral influence from a neoplastic cell line could make it behave in a less malignant way. 
A complementary hypothesis is that T-cells are also infected by XMRV’s resulting in a clonal T-cell expansion. The clonal T-cells produce elevated cytokine levels which may be partially responsible for the CFS. Furthermore these cytokines may have a paracrine activity that would stimulate a simultaneous neoplasm to behave in a more aggressive fashion.

Oncology has been focused on the obvious malignancy and cancer is much more complicated than that. No longer can oncology just treat the obvious malignancy. Attention must be paid to treating the clonal T-cells. It goes without saying that the virus also must be treated. We are just looking at gamma delta T-cells now. There may be other clonal expansions that we haven’t looked for yet: clonal alpha beta T-cells, clonal B-cells, clonal monocyte/microglial cells and clonal mesenchymal stem cells. We are just beginning, but at least we are beginning.

1. XMRV infection induces host genes that regulate inflammation and cellular physiology. Lee M, Gusho E, Das Gupta J, Klein E, Silverman R. J Urology 2011, 185(suppl 4):e 113. 
2. Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Sciamanna I, Landriscina M, Pittoggi C, Quirino M, Mearelli C, Beraldi R, Mattei E, Serafino A, Cassano A, Sinibaldi-Vallebona P, Garaci E, Barone C, Spadafora C. Oncogene 2005, 24:3923–3931. 
3. MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. Katz E, Lareef MH, Rassa JC, Grande SM, King LB, Russo J, Ross SR, Mon JG. JEM 2005, 201:431-439. 
4. Sequences within the gag gene of mouse mammary tumor virus needed for mammary gland cell transformation. Swanson I, Jude BJ, Zhang AR, Pucker A, Smith ZE, Golovkina TV. J Virology 2006, 80:3215–3224.
    Did you like this? Share it:

    11 thoughts on “A Reason For Hope

    1. >Thank you for this ray of light in the storm. I will need to take some time to reread this a bunch of times to really understand it, but what I am understanding, bottom line, is that there is a medical paradigm change afoot – and so desperately needed.

      I think all the wrangling is due, to a significant degree, to the old paradigm fighting back for all it's worth – which is what happens just before a big shift. Whether this is in my lifetime or not is unknown but it makes me feel that my part in the groundswell hasn't been in vain. The shift will happen, there is no doubt. What remains to be seen is the total human cost.

      The other thing I've been reflecting on lately is that people with chronic Lyme have had a pathogen all along and they are essentially in the same boat as we with ME are. A pathogen doesn't appear to be enough to create a change there, either. This loops back to my previous idea about paradigm change since chronic Lyme clearly challenges the "single bullet" theory of medicine that is shooting back at us right now.

      Clearly co-factors and understanding their interactions with each other and the terrain, not to mention other players in the whole context of human health will be needed. My hat is off to you, Dr. Snyderman, for thinking the way you do and sharing it. And thanks Dr. Deckoff-Jones for having this blog and being willing to be a lighthouse in the storms.

    2. >I am probably wrong and missinformed on this, but why is Synderman talking about XMRV, if He just detached his name from the original Sicence 2009 paper because of lab contamination?

    3. >Wow! I can't say I understood all of this, but what I could understand seems remarkable!

    4. >Thank you, Dr. Deckoff-Jones and Dr. Snyderman. This is wonderful news, and it could not have arrived at a more opportune time. I think we all need some good news today.

      Patricia Carter

    5. >Didn't know cytokines can be a trigger for cancer! That does seem the obvious link between ME and cancers.

      So glad to see Dr. Snyderman is continuing with his pioneering work and getting tantalizing clues to our disease!!

    6. >Dr. Snyderman,

      Every time I read something like this from you, I am inspired by your courage, will to press onward, and willingness to share openly with us. Thank you!

    Comments are closed.