Eradicating HMRV (or whatever they name it next)

[mojoey]

I was always intrigued by reports of CFS patients with cancer going through remissions after chemotherapy and Rituximab. One of the more plausible theories for why it put CFS symptoms into remission for some patients is that it eradicated one of the main reservoirs for HGRV in b-cells. However, with our understanding or retroviruses, it is highly unlikely that they are the only reservoirs. The main reservoir for HIV seems to be CD4 memory t-cells http://www.nature.com/nm/journal/v7/n4/full/nm0401_404.html, but they have been found in the following types of somatic cells (not to mention germline cells) as well:

follicular dendritic cells http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=52182
various types of stem cells (progenitor and hemopoetic) http://www.the-scientist.com/blog/display/57203/
astrocytes (glial cells in the brain) http://pag.aids2010.org/Abstracts.aspx?AID=6543
macrophages...and surely many other reservoirs that are yet to be discovered.

In summary:

"Cells of the mononuclear phagocyte system, principally blood monocytes and tissue macrophages, T lymphocytes, B lymphocytes, natural killer (NK) lymphocytes, dendritic cells (Langerhans cells of epithelia and follicular dendritic cells in lymph nodes), hematopoietic stem cells, endothelial cells, microglial cells in brain, and gastrointestinal epithelial cells are the primary targets of HIV infection." - http://library.med.utah.edu/WebPath/TUTORIAL/AIDS/HIV.html

So assuming that HGRV exhibits similar tropism tendencies as HIV (not really a stretch here), we can extrapolate that there are plenty of reservoirs beyond immune system cells and some organs (i.e. prostate). Despite this roadblock to eradication, one application of chemo has been successful, not by eradication but by inducing "lethal mutagenesis" - causing HIV to self-destruct using gemcitabine and decitabinehttp://www.newsmaxhealth.com/health_stories/chemotherapy_drugs_HIV/2010/08/25/344335.html. Peptide T (DAPTA) has also been claimed to be able to eliminate HIV reservoirs.

There seems to be some noticeable momentum toward a combination of HAART and eradication-based approaches in the scientific community. Rituximab is really a form of chemo, so multi-targeted chemo seems to have a place in treatment.

In a collaboration between Dr. Rafick-Pierre Skaly, of the Universit de Montral, Dr. Jean-Pierre Routy of the Research Institute of the McGill University Health Centre (RI-MUHC) and scientists from the National Institutes of Health (NIH) and the University of Minnesota in the United States, Dr. Skaly said:

"Our results argue in favour of a strategy similar to the one used against leukemia, which is targeted chemotherapy, associated with a targeted immune treatment. This would make it possible to destroy the cells containing a virus, while giving the immune system time to regenerate with healthy cells."

In an interview by Franoise Barr-Sinoussi, Ph.D., she summarized both the nature report of resting t-cell reservoirs and Dr. Sekaly's reports by saying:

There is already data indicating that with molecules [that work] against histone deacetylase, you can unlock viral replication. And so, together with antiretroviral treatment, it's another strategy that we can think about for the future. And there are very interesting data in the literature on those aspects.

So my guess is that in the future, in order to control these reservoirs, we will have to combine a strategy to unlock the latent virus in the reservoir cells together with antiretroviral therapy. Another strategy may be to use early intense antiretroviral treatment together with molecules that resemble anti-cancer drugs. But we also have to keep in mind immunomodulators and vaccine therapy for the future when we will have good candidates.

Considering Dr. Mikovits' substantial experience with cancer, I'm sure she is considering cancer drugs as a treatment for HGRV. I just don't know in what context. Hopefully using such detection approaches as the GFP-LnCap culture testing, she can track the migration of HGRV and hence find the reservoirs. This technique will detect both active and latent viruses in the body (GFP is used to track stem cell migration). I hope that she is simultaneously considering blocking replication and eradicating reservoirs with chemo-type approaches that are readily available. Considering the slower replication, "low-copy" status of HGRV versus HIV, I think eradication of reservoirs will actually have more immediate results than HAART. It has been theorized that much the damage being caused by HGRV is the dysfunction they cause by remaining intracellular, whereas HIV causes most of its damage via killing the T-cells and looking for additional cells to infect.

I think stem cells also become begin to have a place in the conversation now. Cheney has only produced 3 cures out of 30+ patients, and it's not clear whether they had HGRV before. Considering the high HGRV positivity in his clinic http://www.forums.aboutmecfs.org/showthread.php?7331-Cheney-Clinic-positive-XMRV-MLV-HGRV-study, this low success rate may have something to do with HGRV. I know he does not like HAART because they kill stem cells, but I think chemo+haart followed by stem cells or variations of this approach should be considered because the stem cells would theoretically repair the damage previously done by either or both.

Here is an outline of a clinical trial on a HAART+stem cell study going on at Duke:

Patients receive a combination of 3 antiretroviral agents beginning at least 3 weeks prior to the initiation of the myeloablative conditioning regimen. The antiretroviral agents are discontinued on days -5 to -1 prior to transplant. Beginning on day 0 the antiretroviral agents are restarted and continue indefinitely. Patients who are given umbilical cord blood (UCB) transplants undergo collection of autologous peripheral blood stem cells (PBSC) prior to the myeloablative conditioning regimen in case there is UCB graft failure.

Would love to get more feedback on this.

 

[Daffodil]

m0joy..u might wanna check out my thread on HIV research...i like the Tre Recombinase approach. doing humanized mice trials right now. takes about 3 years to make a recombinase for a new virus. max plank institute. they were able to eradicate i think 80% of virus from a mouse using that alone. snips HIV out of genome. will be ready for human trials in 10-20 years.

XMRV will, i think, be more difficult to eradicate than HIV. the cells with this virus are much more stable than with HIV. also, looks like XMRV infects a lot more cell types. futhermore, the virus is more tissue-bound.

not sure how cancer therapy can clear latent reservoirs....but i dont know much about this.

 

[mojoey]

Hey Daffodil,,

Thanks. Will check it out.

About the virus being difficult to eradicate, I'm not talking about eradicating the virus directly. I"m talking about eradicating the reservoir. No matter what kind of retrovirus, when you kill the cell, the retrovirus dies. That's why chemotherapy is so interesting to me since it kills immune cells. Chemo can also target other cell types. That's why establishing the reservoirs is an important first step here.

In fact, because of the stability of XMRV, targeting the cellular reservoirs may very well turn out to be a primary treatment approach to relieve symptoms, whereas with HIV you're primarily focused on inhibiting replication to save your life, and then eradicating reservoirs to prevent future breakouts.

 

[jenbooks]

Joey, Luc Montaigner has new research on HIV showing the electromagnetic signature of the DNA for the virus in HIV positive patients on antiretrovirals. Meaning, he concludes (if I'm paraphrasing correctly) the virus shifts its typical RNA-based replication method to create a lurking, DNA based reservoir, when under selective pressure of HAART. That would be why, off ARV's, the virus resumes its normal replication approach and relapse is quick.

No reason to believe other retroviruses wouldn't use the same tricks. Or that homeopathy, if you could use cancelling technology with the same EM approach, ie create an EM wave that would cancel like sound headphones (I'm just dreaming this up) might not work?????

 

[Daffodil]

m0joey..i am confused about what you mean by latent reservoirs. how can they be killed if there is nothing about them that is outwardly different from normal cells?

maybe i dont know what i am talking about..i am very foggy.

 

[mojoey]

Hey daffodil,

You're correct that latently infected cells don't appear to be outwardly different. In that case, the trouble with chemo-based eradication is I think you can't fully eradicate it with chemotherapy without practically killing yourself given the diversity of reservoirs. Researchers theorized that chemo followed by bone marrow transplant and HAART would eradicate the reservoir, but this was shown not to be true:

Negative results on HIV DNA after BMT gave hope of a significant reduction of the reservoir, indeed HIV remission. The organism was repopulated by donor-derived cells that could mount a successful antiviral response through cytotoxic T lymphocytes [3]. Moreover, graft-versus-host disease could have destroyed residual haematopoietic cells potentially harbouring virus [5], including infected macrophages [3]. We did not, however, observe HIV-1 eradication. Unfortunately, the HIV-1 replication recovery a few days after HAART interruption unambiguously showed the persistence of an infectious viral residual reservoir, may be in profound tissues.

- http://www.natap.org/2008/HIV/111908_03.htm

It's likely that barring a vaccine for treatment, "activation-elimination" strategies are neccessary, where you use certain chemicals to induce retroviral gene expression. Here is a great summary of such approaches for HIV:

Given our current understanding of the latent reservoir, it is difficult to envisage a strategy for eradicating HIV that does not contain a component intended to specifically target latently infected cells. Most proposed strategies involve activating these cells in some way to induce expression from the HIV genome. The cell would then be killed either by viral cytopathic effects or by immune effector mechanisms, and virus spread would be prevented by maintenance of HAART throughout the stimulation period. Stimulants that have proved effective in activating HIV from latency in these cells include cytokines such as interleukin (IL)-225 and IL-7.26 Other molecules, such as the non-tumour-inducing phorbol ester prostratin,27 histone deacetylase inhibitors like valproic acid28 and certain modulators of cellular microRNAs,29 are also capable of activating a latent provirus. Unfortunately, none of the strategies that has been tested so far is capable of purging all latent virus, and those techniques that lead to the most robust viral activation are also associated with inducing undesirable generalized immune activation. These limitations highlight the need for further research into the molecular mechanisms associated with activation of HIV from latency. The development of in vitro primary cell models for latent HIV30,31 may provide the opportunity to identify small molecules that could improve the ability to activate and then purge these viral reservoirs. Along these lines, the recently reported32 chemical synthesis of prostratin and its analogues is promising because it should facilitate the development of phorbol esters that activate latent HIV with greater specificity and efficacy than naturally available compounds.

Methods for enhancing killing of recently activated HIV-infected cells are also under investigation. One example of this is the use of immunotoxins. These are molecules composed of a targeting domain derived from a monoclonal antibody linked to a toxic moiety. An immunotoxin specifically targeting cells expressing the HIV envelope protein has been used to deplete both latently infected T cells33 and infected macrophages34 after up-regulation of HIV gene expression with stimulants. ‘Activation-elimination’ strategies such as this may therefore accelerate clearance of HIV from its various cellular reservoirs. Moreover, if this type of approach were used in conjunction with post-exposure vaccination or genetically modified stem cell immune reconstitution strategies, it might prove even more effective in decreasing or eliminating latent and persistent viral reservoirs.

- http://jac.oxfordjournals.org/cgi/content/full/63/1/7

 

[Daffodil]

RE: HIV.....according to one researcher i spoke to, we will first begin to see treatments that block the CCR5 receptor. some docs, like dr. lewin who spoke at the 2010 vienna conference, think we will have a cure before 2020. others, including some top CFS researchers, say you cannot eradicate a retrovirus because all you need is one to repopulate. but even dr. fauci thinks a cure is feasible. most who do think it can happen would say it wont happen for at least another 20 - 30 yrs.

i would like to start a foundation and collect funds for research into eradicating our virus one day....

 

[mojoey]

I don't think it's necessary to emphasize how long various researchers think it will take. In my opinion, if no one knows the answer, why would we rely on anyone's crystal balls? I'd rather glean the scientific expertise from researchers actively involved in the search for answers and form my own opinion. No one knew HGRV would be discovered in ME/CFS until it was discovered. Similarly there's no reason to put a timeline on the concept of eradication.

And let's please be clear that my definition of eradication is not absolute. If eradication means that the circumstances aren't in place for it to arise again, I'll take that. I like the mono apology: most of the population still has mono. It's not "eradicated" in the physical sense, but for people, it is in the sense that immunity has a chokehold on it and it won't come back. I think that's what we should aim for. Germ warfare has rarely been an end-all solution for all but the most simplistic bacteria, so we should focus on terrain warfare instead.

 

[Daffodil]

yes..they are hoping that eliminating most of the reservoirs might enable a body to keep HIV in check on its own.

 

[mojoey]

Since all the hubbub this morning was about Cerus and its intercept system, I wanted to comment on its potential application to treatment. The intercept system is essentially a combination of UVa light and amotsalen, a form of psoralen (a type of plant compound). The psoralen, when activated by UVa, induces crosslinks in the DNA of the pathogen, preventing replication.

The application to treatment is interesting and I haven't really found a good answer yet. Yes it would be impossible to filter all the blood but if the psoralen is injected intravenously and only a portion of the blood is irradiated, the light may disperse once the irradiated blood is transferred back to the patient, and activate the dispersed psoralen. PUVA is a combination of oral psoralen and UVA light shined on the patient, so this is not entirely a green approach.

This would of course cause damage to the healthy genes in our bodies as well, but considering that chemo-type drugs are being used to wipe out HIV reservoirs in addition to HAART, the "damage" is already a given. If this method can somehow be dispersed widely enough to crosslink pathogen DNA in the HGRV reservoirs (understanding that as things stand chemo is unlikely to wipe out all the reservoirs without killing the patient due to the diversity of cellular reservoirs),then I believe it should be considered in conjunction with follow-up stem cell therapy which would plausibly repair the damage done to healthy cells. In summary, if it can prevent replication and stop replication, then it could be a two-headed monster to substitute for HAART and reservoir flushes.

The questions I have are:

1) is the crosslink permanent once induced? Meaning the HGRV genomes that the psoralen+UVA reach would only need 1 treatment?

2) How would this method reach hard-to-reach areas such as tissue/organs

3) Can all the damage be reversed by stem cells, as in the case of chemo

 

[Daffodil]

i thought this was interesting:

"XMRV infection was however not restricted to bone marrow derived cells, but showed distinct target specificities in various organs"

it is from this article:

http://retroconference.org/2010/Abstracts/39855.htm

 

[mojoey]

Based on Cheney's new report http://www.forums.aboutmecfs.org/showthread.php?7507-Dr.-Cheney-comments-on-the-XMRV-workshop&p=121787#post121787 it seems we were correct in assuming that the reservoirs would be nearly ubiquitous. To me, the most important part of his report was this:

Over time, the infections of various organs tended to be cleared by either immune mechanisms but especially by restriction enzyme systems present in almost all human cells that hypermutate the virus so it cannot persist as a competent infectious agent.

My interpretation of this is that our innate preferred method of silencing this particular type of virus is by inducing hypermutation of the virus. This would mean that instead of eradicating the reservoirs, successful therapy might focus on agents that either work on our internal "restriction enzyme systems" or directly hypermutate the virus such as some chemo drugs are doing to HIV http://www.poz.com/articles/hiv_lethal_mutagenesis_761_18990.shtml and experimental drug KP-1461 is doing to HIV http://www.sfaf.org/files/site1/asset/beta_2010_winspr_drugwatch.pdf

Perhaps research should delve into these enzyme systems to see if the virus is affecting them directly, a la the body's inability to secrete macrophage-activating factor (gcmaf) during HIV infection.

 

[slayadragon]

Okay, so it seems these monkeys tended toward clearing the virus from both the viral reservoirs and the blood on their own.

On the other hand, I think that we're going on the assumption that CFS sufferers do not generally clear the virus - maybe not in the blood, certainly not in the viral reservoirs.

What's the difference between us and the monkeys?

For instance, I have a good idea of why our herpes family viruses tend to go out of control. It's because of the low NKC activation. That's the part of the immune system that's supposed to key herpes viruses in check, so with them disabled, the viruses are free to go wild.

Are the restriction enzyme systems in our bodies broken? What would be causing them to be broken?

(I'm not really looking to fix them with drugs, though that would be okay too. But I mostly - for now - want to know why they're not working to begin with.)

Is there some other part of our immune system that would be keeping the viruses under control, if it weren't broken?

Thanks, Lisa

 

[Daffodil]

lisa....you mention that the monkeys tended to clear the virus on their own...can you tell me where you saw this?

thanks a lot
sue

 

[slayadragon]

Joey quoted it above:

>Over time, the infections of various organs tended to be cleared by either immune mechanisms but especially by restriction enzyme systems present in almost all human cells that hypermutate the virus so it cannot persist as a competent infectious agent.

Best, Lisa

 

[dannybex]

I thought it was interesting that Cheney mentioned mold as a possible 'reactivator'.

 

[urbantravels]

One could hypothesize that we unfortunate PWCs do not clear the virus because of some genetic variation or defect.

 

[Daffodil]

wow. i had no idea the monkeys cleared the virus. thats pretty wild.

almost all docs tell me to get the eradication idea out of my head so thats what i am really trying to do...of course it doesnt totally work

 

[leela]

I can't find which thread now, but there's another thread here about DAPTA (a refined peptide T treatment) that's being worked on now by RAPID, that appears to be designed specifically to flush out latent/occult virus. I really feel encouraged that RAPID is aware of the potential use of it in ME/CfS and hope we can channel the funding their way for immediate trials.

 

[mojoey]

Peptide T is interesting indeed, but the reason why I didn't talk about it here is because it works on the CCR-5 receptor, where MLVs seem to use the xpr1 receptor. Candace pert did mention she had some success with cfs patients so it may help through another pathway such as lowering neuro inflammation.

Hopefully a trial will be done on xmrv+ patients anyway. It certainly sounds like she's interested due to her collaboration with ruscetti and company.