Here are more abstracts about XMRV from Belgium which strongly suggest that it is more than a contaminant:
Restricted infection of xenotropic murine leukemia virus-related virus in human lymphoid tissue
Marta Curriu, Jorge Carrillo, Marta Massanella, Elisabet Garcia, Bonaventura Clotet, Julian Blanco, Cecilia Cabrera
Heme oxygenase-1 activation inhibits XMRV pathogenesis and carcinogenesis in prostate cancer cells
A prototype RT-PCR assay for detection of XMRV in multiple human sample types
Ning Tang, Andrea Frank, Robert Kowal, Gregor Leckie, John Hackett Jr, Graham Simmons, Michael Busch and Klara Abravaya
Dr. De Meirleir’s presentation was listed in the Poster Section of the agenda and was called “Serological evidence of XMRV in CFS and blood donors in Belgium”. I don’t believe it’s available online, but certainly look forward to his report.
The take home message from this conference and the recent publications from the point of view of what does it all mean to a patient? If you have prostate cancer, you may be allowed to have it, but if you have CFS, you aren’t. But there are a few fighting for us, Mikovits, Russcetti, Lombardi, Hanson, Snyderman, Bell and co-authors.
If you look at the conflicting papers of which Graham Simmons is a co-author, assuming that you believe that Knox et al is worthy of consideration in light of the various potential conflicts of interest of its authors, the combined findings suggest that blood isn’t the best place to look for XMRV by PCR. The Tang et al paper referenced above is co-authored by more people who work for Abbott. The author’s of the paper looking for XMRV in blood donors (#3 last blog) also work for Abbott; they concluded the positives were due to cross-reactivity with HTLV sequences.
Simmons and Busch work for Blood Systems Research Institute, an institute dedicated to transfusion safety, primarily funded by NIH grants according to their website, apparently a for profit organization; they are also part of the Blood XMRV Scientific Research Working Group, whose abstract (#4 last blog) states they found enough going on with Phase II to keep going, even though it was inconclusive. More evidence that something’s going on, but we don’t know how to look for it yet. The clinical evidence and the first paper above, suggest that lymphoid tissue would be a good place to look. Gut is another likely reservoir, not too difficult to get tissue. The Tang paper looked at paraffin embedded tissue. There’s lots of that to go around, some small intestine of mine in paraffin at the hospital down the street.
#6, 7 and 8 in the last blog represent the kind of work we need to be seeing, to begin to figure out the nuts and bolts. Fascinating how they are going about producing a mouse that expresses XPR1 receptors in prostate tissue. Exploring receptor physiology, and tissue tropism.
Pointing out the connections between various authors and potential conflicts is not coming from some kind of inside information. Everything I’ve noted is readily available on the internet. I don’t claim to know exactly what’s at the bottom of it. Only that it doesn’t add up, the Knox paper being especially suspect, and the people involved suspect by association. The work isn’t going as well or as quickly as it should be, as we need it to, and there seem to be certain entities and individuals coming up with studies which seem designed to fail. There are an awful lot of people parroting negative studies without looking at the totality of the evidence. People attached to HHV-6 as The Cause come up a lot. People attached to it not being a retrovirus. Different individuals have different stakes I’m sure. There’s too much at stake not to bring out the worst in human nature.
If anybody feels the need to write in the comments that I am biased, don’t bother. I am biased. I believe that ME/CFS and related neuroimmune disorders are caused by retroviruses, of which XMRV is likely only one. The other organisms that turn up with regularity are opportunists and copathogens. There are patients that are both culture and serology positive. Contaminant and cross-reacting antibodies with HTLV? My working hypothesis is that we are infected with simple retroviruses that jumped from mice, probably naturally, but then assisted tremendously by the use of animal cells and gene manipulation in tissue culture and nude mice, for various purposes including vaccine production. That starting point for considering my illness has gotten me very far from where I was when I didn’t have that understanding.
At the bottom of this blog are links and excerpts from the NIH online project reporter that are of interest to us. Sandra Ruscetti giving us clues as to why VIP Dx is getting different serology results than those using tests derived from infected monkeys.
Also Ila Singh’s contention that it is present not only in prostate cancer tumors, but in 6% of controls. And she didn’t wonder why she couldn’t find it in anybody’s blood in her new study, including controls? And that didn’t bother her because? It makes me shake my head in disbelief every time I think of it. Scientists like Singh, Knox and Coffin telling people they don’t have the right to treatment based on such flimsy evidence and faulty logic? It’s disgusting.
Maribeth Eiden is an expert in GALV, the only other gammaretrovirus found in a primate. “In addition to being a horizontally transmitted infectious agent, xmrv is a threat to the human genome.”
A clinical trial of IV saline for POTS found its way into my inbox today: http://clinicaltrials.gov/ct2/show/NCT01000350?term=NCT01000350&rank=1. It’s fascinating that doctors in an academic setting taking care of a condition that used to be very rare, but now isn’t, haven’t noticed that it occurs mostly in ME/CFS patients, and seem unaware of XMRV as even a possibility. In any case this approach has had some success anecdotally for keeping ME/CFS patients on their feet, but isn’t practical for most, and like everything, it doesn’t help everyone, including me. It helps Ali a little, but, in general, not enough for the stick, and she doesn’t have enough veins for daily access, nor does she tolerate indwelling lines or FB’s of any kind.
The infusions so far seem very helpful to Ali: more energy, less reactive. I had an adverse reaction to the first one, generalized over-activation, sleep disruption, PVC’s, GI hypermotility, etc. The only thing in the infusion I haven’t had before was Leukovorin, and too much Deplin can cause a similar, though less severe, reaction. It took almost 5 days to resolve and was yet another reminder that sometimes it’s best to leave well enough alone. I did an infusion of glutathione alone about 10 days after the first one and didn’t notice anything. I haven’t been too excited about sticking myself again, since I’m doing amazingly well (knock on wood).
The mild hyperbaric treatments are wonderful for me. I feel great in the chamber, a little slowed after, then really good later on. Ali continues to be sensitive to odors and has stayed away from the chamber because of the new plastic smell. However, the fire burning in Arizona has made the air quality very poor here (in Santa Fe). The horizon is obscured by smoke and there is ash on the ground, though the fire is hundreds of miles away. It burns your eyes, nose and lungs. Yesterday she became short of breath and decided to use the concentrator with a well aired non-rebreather mask at 10L/min. After 20 minutes she felt much better. She repeated that treatment again last night before bed and slept much better than usual, something I notice after each treatment (I’m going in about 3 times/week). Since she tolerates the mask, she can wear it in the chamber and will be protected from any other smells inside the chamber itself. We are both grateful for something so safe that helps in such an immediate way.
Ongoing NIH projects:
In collaboration with the laboratories of Judy Mikovits and Frank Ruscetti, we were able to use antibodies developed against the envelope protein of SFFV to detect infectious xmrv in the blood cells and plasma of patients suffering from the neuroimmune disease chronic fatigue syndrome (CFS). We were further able to develop a seroconversion assay using cells expressing the SFFV envelope protein to detect antibodies against the virus in the plasma of CFS patients. We now plan to apply our knowledge of the pathogenesis of mouse retroviruses that cause cancer and neurological disease in rodents to study the molecular basis for similar diseases associated with xmrv. We are in the process of developing rodent models for determining the biological effects of xmrv in vivo, which if successful will provide a small animal model for preclinical testing of potential anti-xmrv drugs. In addition, we are testing both in vitro and in vivo the biological effects of the envelope protein of xmrv, which like its related SFFV counterpart may be responsible for the pathogenicity of xmrv.
Narrative: xmrv is a new retrovirus that was recently identified from human prostate cancers. This study will attempt to understand the replication of this virus in vitro and its association with cancer. We will explore mechanisms of oncogenesis in cells, in tumors, as well as in animal models, and carry out epidemiological studies to estimate prevalence of viral infection in the general population.
Our lab is recognized for our research on a similar gammaretrovirus isolated from nonhuman primates, gibbon ape leukemia virus (GALV). GALV is the only gammaretrovirus other than xmrv found in primates. In collaboration with Frank Ruscetti at the NCI, Bill Switzer at the CDC and Suzan Winfield and Jessica Siegal-Willcot at the National Zoo, we are investigating the source animal for xmrv, and screening gibbon apes in US zoos for the presence of GALV and xmrv. We have obtained samples from the CDC and the Biological Research Steering Committee that provide us with materials permitting us to determine that many gibbon apes at various zoos have been infected with an xmrv-like virus. We have determined the cell tropism of xmrv using an engineered biologically active xmrv virus with a GFP reporter gene and are identifying cellular factors that restrict xmrv infection of receptor bearing cells. These factors that can restrict xmrv infection will be used as a means of developing xmrv antiviral drugs. In addition to being a horizontally transmitted infectious agent, xmrv is a threat to the human genome. We are in the process of isolating rat germ line cells and exposing these cells to engineered biologically active xmrv virus with a GFP reporter. Sperm obtained from these cells are being assessed. Positive results of sperm expressing GFP indicate that xmrv can be transmitted from infected individuals horizontally (i.e., to offspring as a mendelian trait) as well as vertically through the more traditionally route of viral infection. We used cysteine scanning mutagenesis (SCAM) methods to assess the topology of the GALV receptor and intend to identify extracellular domains of the xmrv receptor using similar methods. These studies will lead to the identification of the xmrv-binding domain. Finally the spread of most retroviruses is mediated not by direct virus infection but by cell-cell transmission from an infected cell to an uninfected cell. We have developed a model system to assess blocks to cell-cell virus transmission using spinning-disc confocal microscopy to visualized individual budding of fluorescently labeled virus particles into adjacent cells in three dimensional space over time.
We have established useful collaborations with Drs. W. Marston Linehan and Peter Pinto (Urologic Oncology Branch, CCR) to study samples from patients with prostate cancer, and with Drs. Frank Ruscetti and Kathryn Jones (Laboratory of Experimental Immunology, CCR) and Dr. Judy Mikovits (Whittemore Peterson Institute) to study patients with severe CFS. As immune deficiency may contribute to infection by xmrv, we have also established collaborations with NIAID to obtain samples from study individuals with immune deficiency, including HIV-infected patients and patients with both HIV infection and prostate cancer. In addition, we are collaborating with Dr. Vinay Pathak (HIV Drug Resistance Program, CCR) in a study of xmrv pathogenesis and prostate cancer as part of a Bench to Bedside Award to Dr. Pathak. Reports of xmrv infection in individuals with chronic fatigue and in otherwise healthy individuals raised concerns regarding new health risks. Within a year of these reports, we have optimized a series of detection and analytical assays with excellent performance characteristics. In the next year, we will apply these approaches to shed new light on the potential role of mouse-related viruses in human disease.
In a related and collaborative project, we have joined Dr, Frank Ruscetti in his studies of the link between prostate cancer and xmrv, a recently-identified retrovirus associated with prostate cancer. Together, we are testing the hypothesis that inflammatory cells serve as a viral reservoir or infection route. We are characterizing the susceptibility of prostate-infiltrating myeloid cells (macrophages and dendritic cells) to xmrv infection. A long-term goal is to identify murine models to study the link between xmrv pathogenesis and prostate carcinogenesis.
D. Vargas et al (Johns Hopkins) demonstrated that individuals with autism and a history of neurodevelopmental regression had evidence of chronic brain neuroinflammation, as exemplified by activation of microglia and astroglia and the abnormal production of inflammatory cytokine and growth factors assayed in both tissue samples and CSF. The authors remarked that chronic microglia activation appeared to be responsible for a sustained neuroinflammatory response that facilitated the production of a number of neurotoxic mediators. Alternatively, neuroglial activation could occur in response to a secondary neurotoxic factor(s) and thus represent the result, rather than the cause, of the injury. Neuroglial activation requires the nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. A small pilot study of minocycline, an antibiotic with known effects on NF-kappaB was undertaken in an effort to determine if the drug might have an effect on autistic behaviors or change patterns of distribution for the CSF or serum cytokines or chemokines. At the doses used in the pilot investigation, no clinically meaningful improvements were seen in behavior nor in the pattern of distribution of the CSF or serum cytokines or chemokines. Thus, no further investigations are planned for minocycline, but the search for novel therapeutic agents continues through the phenotyping study, where longitudinal assessments provide the opportunity to identify biomarkers of neuroinflammation in serial CSF and serum samples and to correlate the results of the assays with clinical symptomatology.
We are also interested in determining the extent to which virus resistance is mediated by polymorphisms of the cell surface receptor. We seek to analyze the XPR1 receptor for the xenotropic/polytropic gammaretroviruses and for xmrv, a xenotropic virus-like virus isolated from humans with prostate cancer or chronic fatigue syndrome.
Some interesting abstracts from the conference in Belgium about HTLV:
HERV’s and MS
Raltegravir inhibitis HTLV
Arsenic trioxyde for ATLL
Ascorbic acid and HTLV
Risk of vertical transmission of HTLV correlates with maternal proviral load.
γδ T cell immunotherapy for HTLV ???
Estradiol and HTLV