EBV infection and inflammation reported to enhance XMRV replication

richvank

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Hi, all.

Here's an abstract of a new paper that presents in vitro work that suggests that Epstein-Barr viral infection and inflammation in general may promote replication of XMRV. Verrrry interesting!

Best regards,

Rich


Journal of Virology, April 2011, p. 3179-3186, Vol. 85, No. 7
0022-538X/11/$012.00+0 doi:10.1128/JVI.02333-10
American Society for Microbiology. All Rights Reserved.
NF-{kappa}B Activation Stimulates Transcription and Replication of Retrovirus XMRV in Human B-Lineage and Prostate Carcinoma Cells{triangledown}
Shuhei Sakakibara,1* Kaori Sakakibara,2 and Giovanna Tosato1

Laboratory of Cellular Oncology,1 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 8 November 2010/ Accepted 20 January 2011

Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-{kappa}B activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-{alpha}), which activates NF-{kappa}B, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-{alpha} and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-{kappa}B activator, increased long terminal repeat (LTR)-dependent XMRV transcription. We identified two NF-{kappa}B binding sites (designated {kappa}B-1 and {kappa}B-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-{kappa}B component p65/RelA. Mutation of the {kappa}B-1 site, but not the {kappa}B-2 site, impaired responsiveness to TNF-{alpha} and LMP1 in reporter assays. A mutant XMRV with a mutation at the {kappa}B-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145, and PC-3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4, and the Burkitt's lymphoma cell line BJAB. These results demonstrate that TNF-{alpha} and EBV LMP1 enhance XMRV replication in prostate carcinoma and B-lineage cells through the {kappa}B-1 site in the XMRV LTR, :balloons:
 

serg1942

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Yes Rich, it is VERY exciting, as XMRV seems to be part of the puzzle. This other abstract completes the one you've posted --showing that XMRV is enhanced by inflammation and other infections--, showing that XMRV, in turn, induces IL-8, so the vicious cycle is established...

http://www.prohealth.com/library/showarticle.cfm?libid=16024

Looking forward to the studies and conferences yet to come this year!!
Sergio
 
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Sure is.

Lots of dots are being joined.
The picture's not too pretty (at least not to a sufferer) but at least it's becoming clear.
 

garcia

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Rich, where does that leave your view that the GD-MCB is the underlying cause of ME/CFS?

Do you now think that XMRV may be the cause with GD-MCB being merely part of the pathology?
 

richvank

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Rich, where does that leave your view that the GD-MCB is the underlying cause of ME/CFS?

Do you now think that XMRV may be the cause with GD-MCB being merely part of the pathology?
Hi, garcia.

Thank you for your interest!

At this point, I think that the GD-MCB hypothesis is still viable to describe the pathogenesis and pathophysiology of ME/CFS. It really has always been a pathogenesis and pathophysiology model. I've always included several possible etiologies (root causes) in this model, any combination of which can deplete glutathione, and from there on, the model goes on to describe how the biochemistry gets disrupted and what the detailed mechanisms are that give rise to the symptoms. Among the etiologies has been what I have called "biological stressors," and these include the pathogens (bacterial, viral, fungal and parasitic) as well as vaccinations, blood transfusions, and a diet deficient in essential nutrients. XMRV would fit there. Whether it's a "first cause" or whether it is exacerbated by something else, such as inflammation caused elsewhere or EBV or other viral infections, remains to be seen, I think.

I do think it is becoming more clear that the partial methylation cycle block is intimately involved with expression of viral and retroviral genes, and that glutathione depletion favors viral and retroviral activity. There appears to be a vicious circle mechanism by which the viruses promote these problems and also benefit from them. I think it's a very exciting time for the development of the understanding of the pathogenesis and pathophysiology of ME/CFS. I'm also intrigued by how the gut-related stuff seems to be coming together with the rest of it.
Here's some stuff to think about: some people have gluten or casein sensitivity, and this interferes with cysteine absorption by the gut. This does two things: it denies the body cysteine, which is the rate-limiting amino acid for making glutathione, and it gives cysteine to the gut bacteria. The latter promotes growth of bacteria that can ferment cysteine, and convert it to hydrogen sulfide. This then is absorbed into the blood and causes lots of problems, including promoting mito dysfunction and impacting the hypothalamus (the latter according to Dr. de Meirleir).

Of course. not everyone has casein and gluten sensitivities, but this is just one way these things are coming together. I think there is a pretty clear connection between GD-MCB and mito dysfunction directly, too, and this brings in the work of Myhill et al. My view is that Pall's work comes out of the methylation cycle partial block, though he disagrees with this. I think Cheney's heart work, the diastolic dysfunction, comes out of mito dysfunction in the heart muscle cells, though he may not agree with this. And Dick Deth's work is supporting the connection between oxidative stress and the inhibition of the methylation cycle. He and I are very much on the same page. Shoemaker's work may tie in by the depletion of glutathione by mold toxins, which has been observed for at least some of them. Also, the ongoing activation of the innate immune system as a result of toxins that the adaptive immune system in some people cannot recognize because of their HLA genotypes would place an ongoing demand on glutathione, I think. It's going to be quite a story when all of this is linked together with all the I's dotted and the T's crossed. What makes it challenging is that some different things are going on in different people. They all do seem to channel together into a partial methylation cycle block, though.

Best regards,

Rich
 

Jenny

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Hi Rich

What is your view of the benefit of IV glutathione? (I'm sure you've talked about this before, but I've no idea where!)

Jenny
 

richvank

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Hi Rich

What is your view of the benefit of IV glutathione? (I'm sure you've talked about this before, but I've no idea where!)

Jenny
Hi, Jenny.

IV glutathione helps some PWME's/PWC's temporarily, and some can't tolerate it at all. For five years I encouraged people to try to build up glutathione by this and other direct methods, but they didn't work as a permanent solution to the glutathione depletion found in most cases. In late 2004 I learned that glutathione depletion is coupled to a partial methylation cycle block in autism, and I immediately suspected that the same might be true in ME/CFS. Experience since then has shown that to be true and that the way to build glutathione up on a permanent basis is to treat to lift the partial methylation cycle block. When that is done, in most cases the glutathione level rises up to normal automatically. However, as I recall, this did not work for you, right?

Best regards,

Rich
 
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Hi Rich,

thank you so much for pulling all these threads together.

Have you by any chance thought about the GC-MAF treatment and the Vit D situation and how this would fit together with the above? Would it only treat the progression of the original stressor, ie virus etc but leave the downstream of meth cycle, mito damage untreated, so that resolution of downstream damage need separate treatment?

many thanks for your thoughts,

Inge
 

Jenny

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Thanks for your reply Rich. I'm very impressed that you remember me!

Yes, you're correct in that the methylation supps didn't do anything for me. The reason I'm asking about IV glutathione is that my doctor has suggested infusions of:

Glutathione and Selenium (not sure how much)
Methylcobalamin (20mg)
Leucovorin (1 Amp)
Intralipid (100ml)

She suggested I have these infusions three times a week for 2 months.

All this would cost over
 

dannybex

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The reason I'm asking about IV glutathione is that my doctor has suggested infusions of:

Glutathione and Selenium (not sure how much)
Methylcobalamin (20mg)
Leucovorin (1 Amp)
Intralipid (100ml)

She suggested I have these infusions three times a week for 2 months.
Hi Jenny,

I'm certainly not a doctor, but that sounds like an extremely large dose of methylcobalamin to start out with.

Kurt is doing well on mb12 (along with other supporting factors) but had to start at 250 micrograms for several weeks before he could tolerate increasing it.

On the other hand, if the standard methylation procotol "did nothing" for you, then perhaps you might be able to tolerate a high dose without any problem. We're all different after all.......

d.
 

richvank

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Hi Rich,

thank you so much for pulling all these threads together.

Have you by any chance thought about the GC-MAF treatment and the Vit D situation and how this would fit together with the above? Would it only treat the progression of the original stressor, ie virus etc but leave the downstream of meth cycle, mito damage untreated, so that resolution of downstream damage need separate treatment?

many thanks for your thoughts,

Inge
Hi, Inge.

Great question! I can only guess at this point, since we don't have long-term data yet on the people who are receiving Gc-MAF. I think that some of them are also doing methylation treatment. My guess is that separate treatment would probably be needed to lift the partial methylation cycle block and raise glutathione, if the vicious circle mechanism has become established, which appears to be true in nearly all cases of ME/CFS that have been tested for the methylation cycle partial block, but that's only a guess.

Best regards,

Rich
 

richvank

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Thanks for your reply Rich. I'm very impressed that you remember me!

Yes, you're correct in that the methylation supps didn't do anything for me. The reason I'm asking about IV glutathione is that my doctor has suggested infusions of:

Glutathione and Selenium (not sure how much)
Methylcobalamin (20mg)
Leucovorin (1 Amp)
Intralipid (100ml)

She suggested I have these infusions three times a week for 2 months.

All this would cost over
Hi, Jenny.

That looks like an interesting combination! It would be supporting the methylation cycle while also boosting glutathione and selenium (the latter needed for glutathione peroxidase). The Intralipid would help to repair the cellular membranes. Would you be the first person to have this treatment, or does your doc have experience with it? Looks like your comment on the cost got chopped off.

Best regards,

Rich
 

Jenny

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Thanks Danny and Rich for your comments.

Danny - yes it is a worrying large amount of methylcobalamin. I haven't had any problems with it at lower doses though - I've been taking up to 5000 mcg a day.

Rich - I think the doc has been using this for some time. The cost for 2 months is over eight thousand pounds (I'm not using numbers as they keep getting deleted.) This is beyond my budget so do you think it would be worth just doing it for a couple of weeks, or would that be a waste of time? And do you think the amount of methylcobalamin is safe?

Jenny
 

richvank

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Thanks Danny and Rich for your comments.

Danny - yes it is a worrying large amount of methylcobalamin. I haven't had any problems with it at lower doses though - I've been taking up to 5000 mcg a day.

Rich - I think the doc has been using this for some time. The cost for 2 months is over eight thousand pounds (I'm not using numbers as they keep getting deleted.) This is beyond my budget so do you think it would be worth just doing it for a couple of weeks, or would that be a waste of time? And do you think the amount of methylcobalamin is safe?

Jenny
Hi, Jenny.

That's pretty costly, alright. Sorry, I don't know whether two weeks on this treatment would be worthwhile or not. It's interesting to hear that your doctor has been using it on other patients. Perhaps you could find out what their experiences have been. I also don't know how your body would tolerate the larger dosage of methylcobalamin.

My fundamental difficulty is that I don't know why the other methylation treatment didn't work for you. Perhaps you have one or more deficiencies in the cofactor vitamins and minerals needed by the methylation cycle. Dr. Klinghardt has found that many of his patients have KPU (HPU), which entails depletion of zinc, B6, and other essential nutrients.

Best regards,

Rich
 

aquariusgirl

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are you kidding me? 8,000 pounds for a bunch of vitamin infusions?that sounds ludicrous.
I've been told glutathione is dirt cheap. I was paying $100 for an IV at one stage (can't remember the amount) & thought that was expensive.

Jam338 has done the patricia kane intravenous phospholipid IVs so you could check out her most recent post.

I just can't see that IV would be that much better than IM & you could get most of the components in the proposed IV in injectable form for much less.

Plus, what happens in 8 weeks?

Lots of us have been injecting B12 and or getting glutathione IVs or suppositories or nebulising for YEARS. It's not a quick fix.
 

willow

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Eek who is this person who thinks they can get away with such charges for so little. I know you're unlikely to say, but I'd like to avoid them :D Seriously, even in the UK that is an unfathomably large fee.

If you don't want to self inject you know you can buy liquid B12 here? Some find they get more result per mg than the SL tabs/lozenges.