If it wasn’t so sad, it’d be funny. Here is a paper from almost 30 years ago that says that a replication defective ERV can be rescued by mixing it up in culture with primate cells: Maturation of murine leukemia virus env proteins in the absence of other viral proteins. Schultz, derived from this work: Molecular properties of a gag- pol- env+ murine leukemia virus from cultured AKR lymphoma cells. Rein.

What a concept! Rescuable incompetent ERV’s. They knew about it in the early 80’s, and knew that there were infectious animal retroviruses in vaccines, but decided not to worry about it. And why can’t these parenterally administered xenotropic and polytropic viruses infect humans? “Because they can’t”. “They are inactivated by human serum.” Now that certainly is sound scientific reasoning. And they accuse patients of poor scientific discourse? Scientists please, take your blinders off. There is a whole generation in which 1 in 100 is autistic.

This is where the science is, if anyone cared enough to apply it to us: Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Macfarlan

Here are a few good ones:

• Risks linked to endogenous retroviruses for vaccine production: a general overview. Dewannieux 
• Isolation of an Infectious Endogenous Retrovirus in a Proportion of Live Attenuated Vaccines for Pets. Miyazawa
• Endogenous retroviruses as potential hazards for vaccines. Miyazawa
• Divergent Patterns of Recent Retroviral Integrations in the Human and Chimpanzee Genomes: Probable Transmissions between Other Primates and Chimpanzees. Jern “According to the “breakout” hypothesis, copackaged RNA of partially defective ERV elements occasionally may recombine, thereby rescuing and optimizing retroviral function during reinfections from within.”

Dr. Anon, PhD thinks I should do nothing for the next 10 years while I, my daughter and my patients deteriorate. We should all just wait while a bunch of jokers at the CDC try to figure out what the questions are. I know what the questions are. Anyone with critical thinking skills that has actually read what I have written on this blog (including the references) should know what the questions are. Whether or not one particular xenotropic MLV exists in humans or not is now quite besides the point. Not finding MLV’s in 8 vaccines that never came near a mouse cell doesn’t support the safety of anything. Even Switzer et al suggest that maybe they should look at batches of old vaccines, though my understanding is that they were mostly used up in the search for the origin of HIV. They also seem to think that maybe the monoclonal antibody folks should take a closer look into their products, e.g. rituximab, produced via an intentional fusion of mouse and human. They’ve been doing this since the ’70’s. Fooling Mother Nature. Would one of the scientists reading like to explain to us exactly how this is done? The literature is confusing.

But Dr. Anon, PhD, reading my blog, wants to “puke” because I am taking properly prescribed drugs for an off label indication? What a world! Tenofovir is prescribed for chronic Hepatitis B. Does that make you want to puke? We have non-HIV, non-HTLV AIDS, exactly analogous to non-A, non-B hepatitis before C was isolated. Wikipedia article: Off-label Use. The off-label prescribing of existing arv’s is completely legal. The only reason to prohibit it is because of the enormous financial implications if it works. Only a very few people have tried it. No disasters yet attributable to it, unlike most of the pharmaceutical alternatives; and to the scientists reading, you wouldn’t believe the dangerous crap my patients come to me taking, in combinations that have no research at all behind them to tell us about possible interactions. In my case, the only adverse effect of my experiment with arv’s that I can point to is that my straight hair became curly; this happens occasionally with chemotherapy and other drugs.

Tenofovir treats Hepatitis B. Raltegravir inhibits Herpesviruses. AZT has been noted to impact Sjogren’s, which seems to be overrepresented in our patient group. Protease inhibitors kill some parasites. I referenced a paper in the last blog in which it was reported that HAART brought about an impressive remission in a patient with advanced MS (and some of us, myself included, have MS light). Those “confounders” are good things about the drugs in clinical practice; all drugs have good things and bad things about them for a given individual. As a clinician, I love it when a drug hits two things in a patient, making it more likely that the cost/benefit ratio for that drug will be favorable for that person. However, the idea that my response to arv’s is because they controlled my Herpesviruses is almost as ludicrous as the idea that Dr. Snyderman’s cancer cells went down because of a placebo effect. Twice.

This seems like a good time to note that I have never had mono and am serologically negative for EBV. Since I was an ER doctor for 16 years and exposed to lots of mono, my body must be pretty good at keeping invaders out. Ali’s EBV tests are consistent with prior infection, and we both have low titer IgG for HHV-6, like almost everybody. There is really nothing to suggest that we have activated Herpesviruses as part of our picture, opportunistically or otherwise. Ali falls squarely into the Lyme group, not the activated virus group, and opportunistic infectious are not really a part of my clinical picture at all. I catch almost nothing. It’s the inflammatory effect of the physiological changes caused by the persistent immune shift to fight viruses so effectively that creates the subjective illness. Patients, and doctors, often confuse the symptoms of persistent inflammation with an active infection that needs to be killed or treated. There is also a subset of patients that catches everything and has ongoing problems with activated viruses. I have heard from people who have had mono and shingles numerous times.

Most novel uses of existing drugs are figured out serendipitously. Somebody with two things takes a drug for one thing and the other thing gets better. Occasionally, somebody actually connects some dots and tries something on purpose. If it gets reported, it is called a case study. In a sane world it would be followed with an open label trial and then a double blind placebo controlled study.

In response to the criticism that I’ve lead thousands of innocent patients down the garden path, please read what I’ve written, before jumping to conclusions. I have never said anyone should take arv’s. My point is that it should not be prohibited, and most definitely, the decision should not be in the hands of a bunch of lab scientists that have never treated a patient. A retrovirologist has no basis for an opinion about treatment at all. That they would presume to comment is a sign of disordered thinking right there.

As I have said all along, ours was never a good experiment. What I have reported here is strictly clinical medicine. We were on an uphill course for about six months before starting arv’s, after quitting Lyme treatment. I do think that antibiotics were making us worse and when we stopped them, we went uphill, though an LLMD might say our treatment had worked:). I believe that arv’s helped us, though incompletely, not surprising for patients that have been sick for many years, who most likely have a high proviral load that continues to replicate mitotically. We still seem to be doing better than might be expected, but I have no way of knowing how we would be at this moment had we never taken them. The only marker we had to follow, TGF beta-1, initially very high has normalized for both of us over a year and a half (see numbers posted here; the pending results from 11/30 were normal TGF beta-1 and elevated C4a, for both of us). It is a very bad disease and we both feel lucky that our suffering is reduced. I wish that the science was keeping up so that we might have a better way of monitoring our therapy. We need a viral load measure or RT assay to follow, understanding full well that we might have more than one virus each and replication incompetent contributors. My biggest concern is the possibility of viral resistance, not toxicity of the drugs.

As far as the arv elist is concerned, I try to create a safe place for patients taking arv’s to discuss their experiences. Occasionally, I answer a question, but mostly, it is patients talking to patients. Everyone on the list, thirty or so of them, decided to take arv’s on their own, and all have their own prescribing doctors, except for a few that live outside of the US. In my practice, since I am willing to prescribe arv’s for an extremely informed patient, I must not be pushing it very hard, since none of my private patients have yet swallowed an arv.

Unfortunately, it is still the patients least likely to respond who are trying it, people who have been sick for a very long time with advanced disease that feel like they have nothing to lose. Much scarier to contemplate, but with a much greater possible upside, is the question of what would happen if newly crashed ME/CFS or ASD patients were treated quickly after onset of symptoms. This obviously needs to be investigated, but in a controlled setting. It will be very expensive to do safely, so is unlikely to happen for either of these conditions (cancer more likely). People don’t like to be wrong and there are lots of wrong, powerful people in this story.

My husband has been acting CFSy lately. When his symptoms flare, I am always impressed that it must be an infectious disease. All four members of my nuclear family have certain common symptoms, e.g. painless ocular migraine, which was a rare condition when I was an ER doctor 17 years ago, and orthostatic intolerance, of a form that nobody had ever heard of a few decades ago. Vascular instability and autonomic neuropathy in four members of a nuclear family, two sick, two not. Husband and wife not even distantly related. I thank God every day that my son isn’t autistic. I vaccinated him selectively, for the wrong reasons, but I have heard from that woman out there who, like me, has CFS and a CFS daughter, plus an autistic son. Is it because I didn’t give him the Hep B vaccine (which is not a live vaccine, but causes persistent immune activation over a long period of time)?

I get letters now and then suggesting that I do not know how horrible polio and other infectious diseases were before vaccines. That isn’t true, I do know. But just because the vaccine program saved many people doesn’t mean that we shouldn’t look at problems that may have been caused by it, and modify our recommendations now for people at high risk, e.g. people with CFS and new offspring of ME/CFS women. We desperately need extensive epidemiological studies to find out what happened when. If you want to look at the bigger evolutionary picture, we have changed nature’s culling process. If you take the starfish parable from a few blogs back to it’s natural conclusion, throwing the starfish back is a mistake, because they are vicious predators that overbreed and damage the reef.

In the meantime, the backlash from the flash of illumination has started. The Mayo Clinic says SSRI’s (which many ME/CFS patients don’t tolerate), sleep meds, GET and ‘therapy’ are what we can have as far as treatment goes. That’s the best they can do for a million sick people? On their website: “More than 3,300 physicians, scientists and researchers from Mayo Clinic share their expertise to empower you to manage your health.” Shame on them. May the doctors that came up with this page never have to get sick, or have their child get sick, with a horrible debilitating disease and be faced with such options. May they find some shred of compassion in their hearts of stone before that fate can befall them.

I am writing to you today from the Louisiana bayou. My husband’s 50th birthday present a couple of months ago was our first RV, and this is our first trip. We have always wanted to try the RV lifestyle, but now even more so, since we love to be in nature and it is the only way that I can still travel comfortably. Our son was just accepted to Tulane with a big scholarship, so we decided to take him to New Orleans to help him decide what he wants to do. Ali didn’t come on this trip, but will come on the next one, shorter and closer to home. The trip has been exciting, to say the least. We survived the worst blizzard in 40 years in north Texas and a tornado warning in southern Louisiana.

I love the spontaneity and limitless possibility of seeing the world this way. Change is usually so difficult with this illness, but everything I need is close at hand and comes with us when we move. The pendulum of my disease continues to swing, as always, while I practice the art of transcending symptoms, living as many full moments as I can. Right now, my husband and son are fishing in the rain. We’ve had the worst luck with weather. Adversity is giving us all the opportunity to practice acceptance and work on our interactions in a close space. Like life, the difficulties have been punctuated by amazing moments; yesterday we watched from our canoe as a small otter caught and fought a huge fish, then defended it from a Great Blue Heron. This part of the country is very wild and alive. When I couldn’t sleep for a while last night, I listened to wonderful, unfamiliar night noises.

And the breaking news? Lo et al just retracted, saying the work was perfect, but the conclusion must be wrong, since nobody has replicated it yet, except for one other lab. Therefore, enough money wasted. Now there’s some ironclad logic for you.

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.

• The discovery of endogenous retroviruses. Weiss
• Precise Identification of Endogenous Proviruses of NFS/N Mice Participating in Recombination with Moloney Ecotropic Murine Leukemia Virus (MuLV) To Generate Polytropic MuLVs. Alamgir
• Human Endogenous Retroviruses in Multiple Sclerosis: Potential for Novel Neuro-Pharmacological Research. Ryan
• Endogenous retroviral genes, Herpesviruses and gender in Multiple Sclerosis. Perron
• Multiple sclerosis-associated retroviral agent (MSRV)-stimulated cytokine production in patients with relapsing-remitting multiple sclerosis. Saresella

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:

• Friendly viruses: the special relationship between endogenous retroviruses and their host. Varela.
• Human endogenous retroviruses in health and disease: a symbiotic perspective. Ryan
• A Paradigm for Virus–Host Coevolution: Sequential Counter-Adaptations between Endogenous and Exogenous Retroviruses. Arnaud
• The role of human endogenous retroviruses in trophoblast differentiation and placental development. Rote

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).

• Tropism, Cytotoxicity, and Inflammatory Properties of Two Envelope Genes of Murine Leukemia Virus Type-Endogenous Retroviruses of C57BL/6J Mice. Lee
• Molecular biology of Friend viral erythroleukemia. Kabat
• Correlation between disease severity and in vitro cytokine production mediated by MSRV (multiple sclerosis associated retroviral element) envelope protein in patients with multiple sclerosis. Rolland
• Multiple sclerosis-associated retroviral agent (MSRV)-stimulated cytokine production in patients with relapsing-remitting multiple sclerosis. Saresella

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.

• Ultrasensitive retrovirus detection by a reverse transcriptase assay based on product enhancement. Pyra.
• Product-enhanced reverse transcriptase assay for replication-competent retrovirus and lentivirus detection. Sastry
• An improved method for detection of replication-competent retrovirus in retrovirus vector products. Uchida
• Human endogenous retrovirus-R (ERV 3) env-like antigens expressed in baboon testes and epididymides. Mwenda

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.

In the 1970’s three independent laboratories reported the presence of a MLRV in sarcoma, leukemia and various lymphomas [1-6]. The MLRV was found only in neoplastic and not in normal cells and was similar to the Rauscher virus. The most recent nomenclature calls this type of virus an HGRV. Surprisingly, the 1970’s body of work was largely ignored for the next thirty years until 2006 when Urisman et al [7] reported a HGRV/MLRV which they named XMRV in some prostate cancer. In 2009, Lombardi et al [8] at the Whittemore Peterson Institute (WPI) found evidence of infection with HGRV/MLRVs similar to XMRV in most patients with the Chronic Fatigue Syndrome (CFS). At present, the Lombardi et al viral findings have been criticized because many laboratories have not been able to reproduce their results. Some retrovirologists have said unequivocally that HGRV/MLRVs do not cause CFS.

The diagnosis of CFS is objectified by using the Canadian Criteria for diagnosis of CFS and by demonstrating a typical elevation of cytokines and chemokines [9]. CFS patients are suspected to have an increased incidence of lymphoid malignancy and brain tumors compared to the normal population [10]. The implication of this is that HGRV/MLRVs may be etiological for both CFS and malignancy. Daniel Peterson’s CFS practice consisted of 300 patients from the 1984 Nevada CFS epidemic. Thirteen patients from this cohort developed various B-cell lymphoproliferative disorders and all that were tested were positive for a T-cell clonal expansion. They were also found to have evidence of infection with HGRV/MLRV at the WPI but this latter data is now in limbo. It was hypothesized that a HGRV/MLRV infection was responsible for the T-cell clonal expansion and that this clonal T-cell expansion might have promoted the development of CFS and malignancy.

Treatment of MLRV associated malignancy has not previously been reported. The retrovirus HTLV-1 associated T-cell lymphoma/leukemia does respond to AZT and IFNa [11, 12]. In addition, multiple human tumor cell lines including breast and ovarian cancers show growth inhibition and apoptosis when exposed to AZT [13, 14]. Several groups reported inhibition of XMRV by FDA approved antiretrovirals including AZT, raltegravir and tenofovir in cell culture [15, 16]. The response of a patient with CFS and a MLRV associated malignancy to anti-retroviral drug therapy would support a role of MLRV in both. We had the opportunity to study such a patient with both CFS and CLL who was positive for evidence of infection with MLRV and was also positive for a T-cell clonal expansion. He had cytokine and chemokine elevations consistent with the diagnosis of CFS. This patient was a Medical Oncologist who was well acquainted with the therapeutic options and guidelines for both disorders and decided to undergo anti-
retroviral therapy.

Results

A patient with B-cell CLL tested positive for antibodies to MLRV proteins. Integration studies are pending. Although not previously diagnosed as having CFS, his symptoms fulfilled the Canadian Criteria for diagnosis of CFS. His elevated cytokine and chemokine levels were consistent with the diagnosis of CFS. He was also positive for a clonal T-cell expansion by both quantitative and qualitative assays for the presence of a clonal TCRg gene rearrangement. He had average prognostic factors with the only potential adverse factor being a trisomy 12 clone. His testing for EBV, CMV, HHV6A and HHV6B was negative. He started treatment with AZT and raltegravir 571 days after diagnosis of CLL. By day 56 of treatment, his cytokine levels had improved (Figure 1). This coincided with improvement in symptoms of CFS which included fatigue, difficulty in concentration and neuropathic pain. His response continued for 9.4 months with no associated toxicity and he was able to work full time. His previously increasing absolute lymphocyte count (ALC), CD 19 cells and trisomy 12 cells trended downward during this period of time. At the start of treatment with AZT and raltegravir, his ALC was 16,348/cu mm and CD 19 cells 11,658/cu mm up from 3,303 at diagnosis. His trisomy 12 cells peaked at 8,490/cu mm day 117 of treatment up from 1,550 at diagnosis. After 285 days of treatment his ALC was down to 10,600/cu mm, CD 19 cells down to 6,015 and trisomy 12 down to 4,558. Subsequently, his counts relapsed despite continuation of AZT and raltegravir. Symptoms of CFS also worsened. Tenofovir was added and all parameters trended down again and symptoms of CFS improved (Figure 2). The ALC peaked at 16,194 at week 3 of treatment and by week 20 was down to 12,324. The baseline CD-19 count was 9,298, trisomy 12 cell count was 8,902 and the ZAP70 count was 3,068. By week 13 the CD-19 count was down to 6,570, the trisomy 12 count was down to 4,374 and the ZAP70 count was down to 591. Week 20 values of these last three parameters are pending. Quantitative data for clonal T-cells became available at the time of relapse and showed a rise in clonal T-cells that appeared to be more rapid than the increase in the CD-19 cells and after the addition of tenofovir both the clonal T-cells and the CD-19 cells trended down but the clonal T-cells appeared to decrease more rapidly (Figure 3).

Discussion

The development of B-cell lymphoid malignancies in 13 of 300 CFS patients suggests that CFS patients are at a several hundred fold increased risk for malignancy compared to generally quoted incidences for the general population. Of these 13 patients, all were positive for a clonal T-cell expansion. They were also positive for evidence of infection with HGRV/MLRVs but this data is now in question.

The greatly increased risk for B-cell malignancy in a potentially HGRV/MLRV infected population may be due to infection of the B-cell line by the HGRV/MLRVs. Retroviruses have been thought to cause cancer by insertional mutagenesis. 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 MLRVs 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” [17]. Spadafaro has shown that reverse transcriptase can cause gene activation and lead to the malignant phenotype [18]. In some retrovirus related cancers, Env [19] and Gag [20] may also be important in malignant transformation.

The finding that XMRV did not cause malignant transformation de novo in tissue culture [21] 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 block viral protein influence in a neoplastic cell line could make the neoplastic cell behave in a less malignant way.

A complementary hypothesis is that infection by HGRV/MLRVs results in a T-cell clonal expansion. The clonal T-cells produce elevated cytokine and chemokine levels which may be partially responsible for the CFS. Furthermore these cytokines and chemokines may have a paracrine activity that would stimulate a simultaneous neoplasm to behave in a more aggressive fashion [22].

One objection to considering HGRV/MLRVs to be pathogenic viruses is that there was previously no explanation as to how MLRVs could have entered the human population. However, early vaccines were prepared by passaging human virus through mice for the purposes of viral isolation and for attenuation. This would have allowed for contamination of vaccines with murine leukemia viruses [23]. The original Yellow Fever Vaccine was made in the early 1930’s by culturing the virus in mouse cerebral tissue [24]. Some patients received both the Yellow Fever virus and infected mouse cerebral tissue. The YF17D strain was used to immunize over 400 million people world-wide over the next 65 years [25]. The U.S. Armed Forces started to vaccinate service men for Yellow Fever during WWII and continued thereafter as per the branch of service and deployment status [26]. The polio vaccination trials in the United States started in 1952. The polio virus strains were initially serially transferred by Koprowski through many passages in mice, cotton rats and primates to achieve attenuation [27]. Olitsky with whom Sabin had a long-term collaboration adapted the type 2 (Lansing) polio strain to mice [28] and the Sabin vaccine contained this strain. Indeed, the patient studied here, received the live oral polio vaccine in the early 1960s, ten years later developed symptoms of CFS and forty years later developed CLL. He also received the Yellow Fever vaccine in the early 1970’s on entering the Armed Services.

In summary, a new patient with both CFS and B-cell CLL was identified. Infection with a HGRV/MLRV was suggested by the presence of antibodies to MLRV proteins. He also was positive for a T-cell clonal expansion and had elevated cytokine and chemokine levels typical of patients with CFS. With anti-retroviral therapy he showed improvement in his cytokine and chemokine levels, CFS symptoms and hematological parameters. Presumably his improvement was related to the anti-retroviral effects of treatment. The progressive improvement of his ALC, CD19 cells and trisomy 12 clone lasted 9.4 months. Despite continuation of AZT and raltegravir his leukemia relapsed. Interestingly, during relapse both the total B-cell count and the clonal T-cells increased with the rate of increase of the T-cells appearing more rapid. A second response was induced by the addition of the second reverse transcriptase inhibitor, tenofovir. Both the total lymphocyte count and the clonal T-cells fell with the rate of decrease of the clonal t-cells appearing more rapidly. At the time of this report the second response is ongoing at 14-20 weeks.

These findings are consistent with the importance of reverse transcriptase in the behavior of the patient’s leukemia and CFS and the potential influence of the clonal T-cells on both these processes. It is possible that inhibiting reverse transcriptase decreased proliferation of both the T and B-cell clones or the effect might be primarily on the clonal T-cells. The rise and fall of cytokines we have documented would be proportional to the absolute number of the clonal T-cells and secondarily could influence the proliferation of the B-cell clone.

Alternative explanations for the therapeutic effect of his anti-retroviral therapy have been considered. One of these is selective toxicity rather than an anti-retroviral effect. Selective toxicity has never before been seen with the hundreds of agents used as cancer therapeutics and seems an unlikely explanation for his improvement especially as the patient had no toxicity at all. AZT, raltegravir and tenofovir have never been shown to have single agent chemotherapy activity so a chemotherapy effect is unlikely to be an explanation. Anti-telomerase activity of the AZT has also been considered, but the rapid response to treatment does not fit the kinetics of depletion of telomeres and induction of apoptosis. Furthermore, an anti-telomerase agent did reach clinical trial and failed to induce remissions. Anti-herpesvirus activity of the antiretroviral regimen is not a tenable explanation of his response as an active herpesvirus infection was ruled out.

There is nothing unique about this patient’s clinical presentation to suggest that his case is any way unrepresentative. His response to anti-retroviral therapy implies that HGRV/MLRVs were etiological for both his CFS and CLL and that anti-retroviral therapy might help other patients with CFS and HGRV/MLRV associated malignancy. Many more patients need to be studied. Ultimately questions that should be answered are what neoplasms are associated with HGRV/MLRVs, will existing anti-retroviral drugs have activity in these neoplasms, will other anti-retroviral drugs such as a protease inhibitor be required and what would be the optimal combination of anti-retroviral drugs.

As you might expect, the spectacle in Reno, has cost me some sleep. The WPI has fallen on its own sword in an agonizing display of poor judgement. Such a waste of promising research, money, energy, goodwill. Doors shutting tight all over the place. Tragic beyond belief. Judy Mikovits is my friend. I still do not know the details of what happened, as she is prevented from discussing the case by her attorneys. But whatever she did or didn’t do with respect to the events since her firing, it is safe to say that she in no way deserves what is happening to her now. On this point, John Coffin and I agree.

It is all well and good to say that now that XMRV is dead, science can get back to its orderly, stepwise process; they even get to say, we told you so. And I say what I have said all along: millions of patients need treatment now. It is not a static situation. It is a progressive disease, slow, but lots of people are circling the drain. Many new cases that might be easier to treat sooner rather than later… that might respond more completely to arv’s. New babies being born with it. Should we wait a decade to start to find out, in a systematic way, if existing treatments might not affect it? It is incumbent upon the medical and pharmaceutical industries to think about the disease in concept and find solutions, not sit there doing nothing until Virus X is found; that approach already hasn’t worked for decades. It is quite likely that it won’t turn out to be a one virus, one disease, one treatment paradigm. If it were that simple, it would have been found already. So I find myself sitting with real patients, in the here and now, framing the illness as I have outlined here over the last year and a half. I still find the model we are evolving useful in a clinical context.

In my last practice, my interest was peak performance with respect to brain function, no matter the degree of injury or illness. I worked with the things that I found useful, personally and for my patients, most of whom had already exhausted their medical options. I was undiagnosed at that time. I knew I was sick, but it wasn’t too bad, and I knew that conventional medicine had nothing to offer me. It occurred to me now and then that I had some sort of less than MS. Other possibilities occurred as well. I tried to fit it into PTSD, but there were too many physical manifestations, hypertensive crises, arrhythmias, atypical migraines, malaise, this or that instability. I could exercise without problems for a decade. I used to say that whenever something went wrong with my body, it was undiagnosable. And I was CFIDS aware. That state of not knowing made me well suited to being a doctor of last resort. My armamentarium then was HBOT, neurofeedback, nootropics (cognitive enhancers), nutraceuticals, herbs and bioidentical hormones. I found discontinuing unnecessary drugs to be a powerful treatment modality. And I tried to create the space for the less tangible, but no less powerful healing that can happen in the context of connection and relationship.

So far, I am using pretty much the same gentle, yet powerful modalities that I used before, when I didn’t know what I was doing:), and I’m having some beginner’s luck. I am turning to these treatments first, because I know from experience, they work, and now I have a framework that gives me a better idea why. Pulsed, high dose normobaric oxygen is the most powerful and easy to deliver treatment that I have to offer. My patients so far are pretty uniformly impressed. Nobody that has rented a concentrator for a month has returned it, unless to buy one. Responses range from a little helpful to “wow”. There is a short term effect and a long-term additive effect, as I observed with HBOT in practice. It seems one of the craziest things in all this that such a simple thing has been denied us. I wonder about why, and can’t come up with much. It will never be studied, because it can’t be patented. It might accelerate aging, but the longevity folks think it’s the opposite. It needs to be more carefully dosed for patients with seizures and a few other things. Mostly, it’s probably because doctors don’t understand the gas laws, and so are uncomfortable with it. They can handle it when it comes out of a wall in a hospital, where it’s use is sanctioned, and there’s a respiratory therapist to hook things up. Otherwise, if you have COPD or are dying, you can have it. Sometimes insurance will cover it for cluster headaches, or migraines, common in our patient group. I am prescribing oxygen, for an hour a day and prn, at 10L/min by non-rebreather mask (has a reservoir and check valves), or 5-6L/min by simple mask for patients who bought lower flow concentrators (two are improving with this).

Here are a couple of references that address the oxygen paradox: Why might high dose oxygen be good for us, even though we have increased oxidative stress at baseline?

Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. Davies: Cells, tissues, organs, and organisms utilize multiple layers of antioxidant defenses and damage removal, and replacement or repair systems in order to cope with the remaining stress and damage that oxygen engenders. The enzymes comprising many of these protective systems are inducible under conditions of oxidative stress adaptation, in which the expression of over 40 mammalian genes is upregulated.
HIV: reactive oxygen species, enveloped viruses and hyperbaric oxygen. Baugh: ROIs repeatedly have been shown to be virucidal against enveloped-viruses, like the human immunodeficiency virus (HIV). Hyperbaric oxygen therapy (HBOT) increases the production of ROIs throughout the body, leaving no safe harbor for the virus to hide outside the genome. This technique already has been tried on acquired immune deficiency syndrome (AIDS) patients, with exciting results.

As I am finishing my first six months of practice, Ali is coming into her own, with great courage. She has enrolled for an online undergraduate program at U Mass, and will start next month. She has been dating, but still mostly staying home rather than venturing out. Right now, she is deep in the process of confronting that she is probably physically able to do more things away from home, but confined by habit and the limitations of the past. It is hugely more difficult for her than for me to emerge, without a former life to go back to.

Ali credits oxygen and modified Meyer’s cocktail infusions with her slow but continued improvement. She tells me when she feels the need for an infusion. We are still tinkering with the best formula for her. She uses oxygen 4-5 times a week, according to her own instincts. She has come to use it prophylactically for PEM, when she knows she’s overdone it. It is impossible to know what role antiretrovirals are playing in maintaining her gradual improvement which began with the cessation of Lyme treatment and was also obviously impacted by Deplin and treatment for PCOS (polycystic ovarian syndrome). Our concentrator has been broken for a couple of weeks and when the replacement came, she grabbed the mask, exclaiming “Oxygen! Mana of the Gods.” For me too, oxygen is the most tangible thing I have. It impacts my sleep directly.

I asked Ali if she’d like to write something for the blog, and she said it has become too contentious for her to want to risk it. However, she said that if she was going to write, it would be about the things that she has gained from her illness. The silver lining. The wisdom that comes from living life with the toughest teacher always at your side. For one so young, she has become really good at making lemonade. I am very proud of her.

The markers we chose to follow when we started arv’s, beyond what was going to be monitored at the WPI (NK cells and cytokines), were TGF beta-1 and C4a. Ali’s were normal when checked a couple of months ago. The specimens require special handling, several were lost for both of us in 2011, as often happens with esoteric tests; we weren’t motivated to go in for redraws, since they didn’t seem exciting in terms of guiding treatment, and weren’t needed for safety. Ali had no subjective inflammatory flare when she went on arv’s, but most who have tried them, did, usually 6 weeks or so, shorter for tenofovir. Ali’s numbers actually look like she did flare, though clinically she felt she was improving. My impression while I was watching these labs come in was that they were lagging behind the clinical picture. It looks like I flared in August 2010 and interestingly, I was about to leave for my first trip to Reno, first trip anywhere in years, when those were drawn.

click to enlarge

TGF beta-1 is a peptide involved in many cellular functions, including the control of cell growth, proliferation, differentiation and apoptosis. Here is a recent paper suggesting TGF beta-1 as a marker for CFS: Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. Zhang. It is tempting to speculate that TGF beta-1 could be involved in the clonal expansion we are starting to think about with respect to the pathogenesis of ME/CFS and related leukemias; not forgetting that simple animal retroviruses replicate mitotically, by clonal expansion.

TGF beta-1 is implicated in the pathogenesis of Marfan’s Syndrome, which my husband’s uncle, husband and son have; in our family it appears to be more obviously expressed in each successive generation. Elevated TGF beta-1 is implicated in the pathophysiology of Marfan’s. My husband and I both had different, subclinical manifestations of illness when we met, but most, though not all, of his were attributable to Marfan’s. Marfan’s is an autosomal dominant genetic condition where chromosome 15 encodes for a defective protein which is necessary to bind TGF beta-1 to keep it sequestered to normal levels (oversimplified model). Losartan, an ARB (angiotensin receptor blocker) has been shown in clinical trials of Marfan’s patients to lower TGF beta-1 and slow the onset of the most serious consequence of the disease, aortic root dilatation. My biological father had a body habitus consistent with Marfan’s and I may be an Ehlers Danlos variant, becoming more flexible with age and exacerbations of illness. I have minor features of both conditions. Both Marfan’s and Ehlers Danlos seem to be over-expressed in the ME/CFS patient group, already showing up in my tiny practice. Here is an excellent article which considers related disorders with respect to abnormal TGF beta-1 signaling: Transforming growth factor-beta signaling in thoracic aortic aneurysm development: a paradox in pathogenesis. Jones/Ikonomidis.

I still think what I thought. The Whittemore’s have destroyed a very talented scientist, through the most incompetent management imaginable. And now Max. From my vantage point, the whole thing seems to have spiraled out of control after Dr. Lipkin’s visit. My guess is that the patents and saving VIP Dx/Univex are at the bottom of it all. As Annette likes to say, “Follow the money”. Or in this case, the lack thereof. As Harvey allowed me to say in the blog about VIP Dx, he doesn’t have more money to pour into this, since the real estate market went south. Now I imagine they feel entitled to recoup their investment. VIP Dx brought them down. It all began with good intentions, but they have lost their way, in my opinion.Here is the first email I ever wrote to the WPI, dated 10/28/09, after learning that commercial testing was being offered, before I met Judy in Jan 2010:

I am trying hard to think of WPI as a resource full of people who want to help, when nobody else has. But it has come to my attention that the lab that is doing the testing has a financial tie to a member of your board of directors. I am broke. I think four members of my immediate family will test positive for this or another similar virus. I pretty much know that anyway, without the test, but it might make a difference to my disabled daughter to be able to walk into a doctor’s office and say, “I have Virus X”. And I can’t even give her that, at the moment, because her acute medical problems have to take precedence.

I know a conflict of interest when I smell one. Shame on you.

Jamie Deckoff-Jones, MD

Their PR person answered that Annette Whittemore would contact me directly, but she never did. And there you have it. It never changed. She is non-responsive. Doesn’t answer email or phone calls. I’m sure lots of you out there can verify that statement. Her voicemail is often full. She disappears for long periods. Can’t make a decision to save her life. And when she finally does, it was generally the wrong one, in my opinion. I never signed a contract; she spun her wheels about it for months, but never managed to actually give me one. Even so, I wrote nothing after I was fired, except that I’d gotten a “pink slip”, until Judy was fired. Though I knew how terribly flawed it all was, my opinion at that time was that it was better for the patient community for them to exist. But without Judy, it is just a black hole.

I’m not sure exactly what went wrong with the BWG, but part of it was an attempt to validate their commercial assay at the same time. So again, they shot themselves in the foot over the commercial lab. When Lipkin came to dinner, Annette told him she had 19 people on the payroll. Judy had Max and Cassie, both without graduate degrees. And then just Max. Annette has a personal assistant.

Many have asked me what happened with me at the WPI. Here it is, and then I hope I am done writing about the WPI. I have good things to report from my practice, which is what I should be writing about. I can’t tell you all how badly I would like to be done with this. My goal in writing this blog was to be of assistance, not be an energy suck, which is what this whole sordid affair has become.

I became involved with the WPI, because patients corresponding with Judy were sending me her answers to medical questions. I told her that answering those kinds of questions was a reflex for me, and since she was really bad at it, she should let me do it. She thought it was a great idea, but that I needed to have an official relationship with the institute. So I became ?; don’t even remember the title, but it was an official, volunteer position that enabled me to respond to patient information questions.

Without reviewing our email for dates, in late 2010, since the clinic seemed dead in the water, I presented Annette with a model for structuring it, fashioned after emergency medicine groups, generally a contract held by the physician group. It’s set up that way to protect the institution from medical liability. Annette loved the idea and asked me to make it so. An LLC was formed and we hired a physician recruiting company who started to send candidates. I wanted to set it up as a primary care clinic with specialty back-up. I was looking for competent doctors, not specifically CFS specialists. It is one very homogeneous disease after all (I can hear the gasps from here:). Annette expressed her relief to have me, saying that she knew she couldn’t evaluate doctors. She acknowledged that she knew nothing about running a medical practice.

On 3/23/11, already in conflict, I sent this to Annette in an email:

A good administrator:
1. Knows what she doesn’t know.
2. Knows how to delegate.
3. Protects the talent.

She said I was mean. I said I’m the best friend you have. You are paying me to be a consultant and I’m telling you what I think.

I provided a rough spreadsheet, with some numbers provided by the WPI accountant, that showed roughly a million dollars a year in profit with 10 doctors, which would be donated back to the institute for research. The budget asked for $100,000 up front, to be quickly repaid, which included my salary prior to opening. I even said that it was possible to get it open with no money, if I paid the doc’s a percentage of gross, the way we did in the ER. I thought the distribution of expenses at the WPI seemed not in favor of producing any meaningful science, so I do admit to wanting to have a say in how the money was used. I expressed this to Judy, but not to Annette, though she probably sensed it. There was no evidence of a presence of a board of directors that I could detect at all when I was there.

I went to Reno to interview doctors in early spring. Two weren’t right, but Chitra Bhakta was perfect. However, 15 minutes before Chitra arrived, Annette informed me that she had seen new lawyers in Las Vegas and had decided to employ the doctors rather than structure it as a separate corporation. I told her that I thought it a serious mistake for her to employ or try to manage doctors directly. Managing doctors is like herding cats, having done it before. Before my first crash, I was a 20% owner of an emergency medicine contract group and medical billing company in San Jose, CA. My 4 partners and I had 3 contracts and were responsible for 150,000 patient visits per year. I was vice president of human resources. I was responsible for recruiting, hiring, firing, knee-capping. We had 50 doctors and 20 PA’s. I was, in fact, the right man for the job at the WPI. Though sick, I was willing to go down for it. I figured I could last at least long enough to get it up and running, find an onsite director. Getting fired saved me from myself, but I wanted to offer treatment to those 2000 people on the interest list. I wanted to develop a large database, so we could look at treatments in a systematic way. And Judy and I were planning the first clinical trial of tenofovir.

So Annette decided to employ the doctors, including me. I said, it’s your baby, structure it however you like, but let me get to work. My attitude was that I owed her a debt of gratitude that could not be repaid and I would do what she needed me to. We agreed that Chitra should be the first hire. I told Chitra she was hired and that Annette would be in touch with a contract. Well, six weeks passed and no phone call to Chitra, no contract, nothing.

I was planning another recruiting trip. I had at least two interesting doctor candidates, as well as a nurse. I also had a couple of practice manager possibilities. Quite a few of the interested candidates for staff positions were a little sick, which Annette wasn’t happy with, but as it was with me, that’s what there was, except for training newbie primary care doctors. No famous CFS doctors were stepping up to the plate, except for Dr. Enlander who called me and offered to fly to Reno on a regular basis to teach. The other thing we locked horns about a bit was that my approach is non-invasive with respect to treatment choices. I have a strong bias against treatments that can kill, as well as unnecessary invasive procedures when there is plenty of necessary tissue harvesting happening in patients that would be happy to help. But it was always clear that I would not be determining protocol for other doctors. That was never the idea. I was actually thinking that with different doctors doing their own thing, the database would help us sort it out.

Shortly before that trip, Annette pulled the plug all together, deciding that there would be no clinic. Rather doctors would lease space and have their own practices. When I went to Reno for the Lipkin visit, I spoke to Dr. Fredericks and asked him if he would consider using Practice Fusion, free EMR, for the patients that he saw from the WPI wait list. I was still hoping to create the database somehow.

I also asked and received permission for Chitra to see patients under the same deal as Dr. Fredericks. After discussion with Chitra, Annette agreed, then, never got back to her, again. From what I could unravel after the fact, the WPI lawyer somehow decided there was something wrong with her credentials that would prevent her from getting a NV license. Chitra did her internship in NV and then her residency in California. Her NV license needed to be reactivated, but there shouldn’t have been a problem with it. Precisely the kind of thing they needed an administrator for, but they fired me, so there was nobody bird dogging it that had a clue about the sytem. In the meantime, Chitra’s father died and she had to go to India. By the time she got back, the WPI had decided that there was some problem with her. It seems they have even damaged her reputation with this nonsense. In the midst of all this, I was fired, “because we don’t need a clinical director”, but asked to still volunteer, to write for their website or something. I think it happened because Annette is a control freak and couldn’t stand the thought of not calling the shots for the clinic. She did pretty much the same thing with the research, as far as I can tell.The Whittemore’s went public saying that Andrea takes a pill that makes her well enough to work and exercise, but wouldn’t say what it is. So patients, sending in their $10/month from their social security checks can’t even know, let alone hope to access what Andrea has. I expressed my opinion on multiple occasions that this was wrong and an exceedingly poor decision on many levels. It would have been fine to say nothing, but to use it to bolster the reputation of the institute, without disclosing what that treatment is was disgusting. And then Annette lying on the news about all the miracles happening. Using another patient similarly. We got her out of a wheel chair, but won’t disclose her treatment… Fairy dust. My loyalty is to the patient community and I am feeling guilt about saying too little, not too much. People have a right to medical privacy and certainly saying nothing was an option. Many, many people have asked me, but it is not my place to disclose anyone else’s treatment. I never have and I never will. However, as I said to the Whittemore’s, being a public figure has it’s responsibilities and this went down with typical ineptitude.

I am not going to guess what happened with respect to the notebooks before speaking to Judy. The black and white thinking displayed here and on FaceBook is telling. Even poor Lilly Meehan, the sweetest woman on earth, is collateral damage. If Judy isn’t a saint, then Annette must again be one, and Judy now has to be the sinner. All black and white. The reality is all shades of gray, imperfect people in an imperfect world. Epic fail. And that includes me, since I was briefly on the payroll. No matter what just happened with the latest chapter of this disaster, it was very unfortunate that Judy was hogtied by incompetence the entire time. Annette should have stuck to her fund raising activities. But she doesn’t know what she doesn’t know. It was like Keystone Kops. Amateurs. And who are the biggest losers? As usual, it’s the patients.