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Xmrv the puppet master and the master switch>

Discussion in 'XMRV Research and Replication Studies' started by Gerwyn, Apr 27, 2010.

  1. Gerwyn

    Gerwyn Guest

    Nat Genet. 2002 Feb ;30 (2):221-6 11818964 Cit:39
    Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice.
    [My paper] Toshimasa Yamauchi, Yuichi Oike, Junji Kamon, Hironori Waki, Kajuro Komeda, Atsuko Tsuchida, Yukari Date, Meng-Xian Li, Hiroshi Miki, Yasuo Akanuma, Ryozo Nagai, Satoshi Kimura, Takeyori Saheki, Masamitsu Nakazato, Takeshi Naitoh, Kenichi Yamamura, Takashi Kadowaki

    TAKE HOME MESSAGES

    XMRV BINDS WITHIN THE CREB GENE..

    OK WHAT DOES THAT MEAN

    Mitochondria are our batteries that generate the power that our body systems need to operate properly

    The easiest way to visualise the action of CREB is like a switch in a circuit.

    If the switch is off even though the battery is fully charged no current can flow and no work can be done.Once the switch is turned on(CREB phosphorylated by ATP) the various biosystems in the body power up in a controlled way.

    If one other other hand XMRV becomes integrated the switch can become faulty .This can cause "short circuits" or power cuts or turning on and off at the wrong times. It is a bit like every electric household item going crazy throwing sparks teely picture going on and off miccrowave bleeping etc

    The other message to take from the paper is that CREB regulates the production of sterols.

    The most commonly known sterol is cholesterol whose levels are frequently elevated in people with ME.Sterols are also the "reenforced concrete" of our cellular structures.

    Defects in their production could theoretically end up with "Leaky" cell walls just about everywhere particularily in the gut.
  2. serenity

    serenity Senior Member

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    interesting...
  3. Kati

    Kati Patient in training

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    How about correlation with people that either lose weight and those that gain weight during the course of the disease? I mean if the switch is off, no energy is produced, fat is stored for later use, if the switch is on but it overdrive, stored fats are being used up and the person loses weight... does that make sense?
  4. gracenote

    gracenote All shall be well . . .

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    Thanks so much, Gerwyn, for these:

    TAKE HOME MESSAGES
    OK WHAT DOES THAT MEAN

    It kind of, sort of, maybe, helps to make some sense of it all to me.

    Thanks.
  5. lululowry

    lululowry Senior Member

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    Thank you Gerwyn! This is very helpful. And incidentally, when my doctor diagnosed me with CFS, he described what was going on in my system as if all the switches have been turned on (the master switch gone haywire) and now we have have to figure out how to turn each system off again (appropriately). I have such terrible brain fog it just makes me cry with frustration sometimes that I cannot understand this stuff better - so I appreciate this more than you can imagine.:thumbsup:
  6. jewel

    jewel Senior Member

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    I appreciate your posting these science articles/abstracts, and even more, your providing simplified explanation. It makes sense there would be some kind of mitochondrial connection... The notion of switches misfiring--- left on or stuck on off-- or all of this chaotically and unpredictably characterizes our experience. thanks, J.
  7. Gerwyn

    Gerwyn Guest

    makes sense to me i will do some digging
  8. HopingSince88

    HopingSince88 Senior Member

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    Kati-your question about weight is a good one.
    Gerwyn-Thank you for researching these things for us.
  9. Noro

    Noro

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    Hmmmm...i have m.e. but low cholestrol, and was under the impression that people w m.e. had a tendency to have low rather than high, cos i've met others w the same.... ??
  10. vdt33

    vdt33

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    Great article, Gerwyn! "[My paper]" ? Please explain.

    In my family, cholesterol levels are unusually low -- 115 to 150. When one of my doctors saw my cholesterol level, he said "You are going to live to be 110!" Haha!

    These chemicals and ATP are tied into the methylation cycle and glutathione production in some way. I think I remember reading that if you need energy, you don't make glutathione?? I have to get out my Amy Yasko books.

    I am so desperate for any new information about XMRV. You get a gold star today and a hug.

    :hug:

    :D

    vdt
  11. ukxmrv

    ukxmrv Senior Member

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    I am XMRV+ low cholestrol (my family are all low) and I am very overweight. Been ill for over 25 years and was light when I first became ill.

    The weight has steadily pilled on and is not affected by calorie intake or exercise. There were times over the decades when I tried GET and this had no effect on my weight (I just got much sicker instead). Before ME I could diet/exercise lose weight etc.
  12. Gerwyn

    Gerwyn Guest

    Thankyou XMRV I am very much in the same boat.Calorie intake has no effecteither.I will try and do more research.

    Take care
    Gerwyn
  13. Gerwyn

    Gerwyn Guest

    www.ncbi.nlm.nih.gov/pubmed/18424767

    CREB controls cholesterol homoeostasis particularity in the brain.low cholesterol not a good thing here!.Creb abnormalities can lead to the dysregulation of cholesterol synthesis so v low and v high levels are possible


    Creb is also implicated in controlling number of fat storing cells.The more of these you have the more weight you put on even if calorie intake not excessive
  14. Rosemary

    Rosemary Senior Member

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    Hi Gerwyn,

    Thank you so much for this information
    Do you think XMRV also needs cholesterol for its reproduction ?

    eg Cholesterol is needed for HIV-1 production

    Quote " Human immunodeficiency virus type 1 (HIV-1) relies on cholesterol-laden lipid raft membrane microdomains for entry into and egress out of susceptible cells."
  15. Gerwyn

    Gerwyn Guest

    yes i think it is very ossible i have seen that paper and it illustrates the mechanism of cell cell transfer evading the immune systems clutches.MuLvs also do this and XMRV is a MuLV class virus
  16. Rosemary

    Rosemary Senior Member

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    Gerwyn,
    This cholesterol connection is very interesting.....
    Have you read about the twins with NPC ? The twins with NPC also tested positive for XMRV

    Journal Of Virology Reports On Link Between HIV and Niemann Pick Cholesterol Gene: Intact Intracellular Cholesterol Trafficking Pathways Mediated by NPC1 are Needed for Efficient HIV-1 Production

    June 5, 2009 by Chris Hempel http://addiandcassi.com/category/news
    Journal of Virology
    May 27, 2009

    Deficiency of Niemann-Pick type C-1 Protein Impairs HIV-1 Release and Results in Gag Accumulation in Late Endosomal/Lysosomal Compartments

    Tang Y, Leao IC, Coleman EM, Broughton RS, Hildreth JE.

    Human immunodeficiency virus type 1 (HIV-1) relies on cholesterol-laden lipid raft membrane microdomains for entry into and egress out of susceptible cells. In the present study, we examine the need for intracellular cholesterol trafficking pathways with respect to HIV-1 biogenesis using Niemann-Pick type C1 deficient cells (NPCD) wherein these pathways are severely compromised, causing massive accumulation of cholesterol in late endosomal/lysosomal (LE/L) compartments.

    We have found that induction of an NPC disease-like phenotype through treatment of various cell types with the commonly-used hydrophobic amine drug U18666A resulted in profound suppression of HIV-1 release.

    Further, NPCD EBV-transformed B lymphocytes and fibroblasts from patients with NPC disease infected with a CD4-independent strain of HIV-1 or transfected with an HIV-1 proviral clone, respectively, replicated HIV-1 poorly when compared to normal cells.

    Infection of the NPCD fibroblasts with a VSV-G pseudotyped strain of HIV-1 produced similar results, suggesting a post-entry block to HIV-1 replication in these cells. Examination of these cells using confocal microscopy showed an accumulation and stabilization of Gag in LE/L compartments. Additionally, normal HIV-1 production could be restored in NPCD cells upon expression of a functional NPC1 protein, and overexpression of NPC1 increased HIV-1 release.

    Taken together, our findings demonstrate that intact intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.
  17. Gerwyn

    Gerwyn Guest

    yes Rosemary I was going to post the paper in relation to a query from Natasa but you have beaten me too it .Its intersting that the origin of this ability appears to be within the gag and pol genes which all retoviruses have.

    No i had not heard about the twins I will read.did they have xmrv?
  18. JillBohr

    JillBohr Senior Member

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    Columbus, OH
  19. Rosemary

    Rosemary Senior Member

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  20. Rosemary

    Rosemary Senior Member

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    Further information here:

    Researchers establish a connection between NPC and HIV

    The Scientist: NewsBlog:
    New non-drug fix for HIV?
    Posted by Alison McCook
    [Entry posted at 30th June 2009 02:53 PM GMT]

    Researchers are slowly establishing a connection between an extremely rare genetic disease and HIV -- and homing in on a safe, non-prescription compound that could treat both.

    Recently, James Hildreth at the Meharry Medical College School of Medicine in Nashville, Tenn., and his colleagues found that cells affected by Niemann-Pick Type C (NPC), which disrupts cholesterol trafficking, were unable to release HIV, suggesting these cells would not spread the virus.

    These findings, published May 27 in the Journal of Virology, are rooted in a hypothesis Hildreth has explored for a long time: that "cholesterol is somehow essential" to HIV, he said. For instance, HIV-1 relies on specialized structures known as lipid rafts, which are rich in cholesterol, to infect new cells.

    That line of thinking has led him to investigate whether a compound widely employed by the food and chemical industries (and used as a drug solubilizer) which depletes cells of cholesterol could serve as a preventative agent -- or even a treatment -- for HIV. And his growing body of evidence is suggesting the compound, known as cyclodextrin, might do just that.

    "There are very few [compounds] that rival the safety profile" of cyclodextrin, said Hildreth. If further research confirms it has an effect on a disease that affects millions of people worldwide, that would be a major advance, he noted. "It's been exciting for me from the beginning."

    Cyclodextrin appears to also show some benefit in NPC, pointing further to a connection between HIV and the rare genetic disease. Indeed, a family with identical 5-year-old twins with NPC recently received permission from the US Food and Drug Administration to give the girls regular infusions of cyclodextrin. NPC leads to marked abnormalities in the liver and brain and is invariably fatal.

    "You have no idea what a relief it is to have something to try," said Chris Hempel, mother to Addi and Cassi. The girls have so far received several infusions, starting with one continuous 4-day infusion, and are now getting a series of 8-hour weekly infusions of increasing doses. Hempel said the girls improved remarkably after the first 4-day infusion, showing better control of their head and neck and better balance, and were more affectionate and responsive to people. These improvements waned a bit once the girls switched to weekly doses, but seem to be returning as the doses increase.

    In a previous experiment, Hildreth and his colleagues found that adding cyclodextrin to uninfected cells to deplete cellular cholesterol warded off HIV infection. Restoring normal cholesterol levels removed that protection. In a mouse model of HIV, cyclodextrin prevented vaginal transmission of the virus by infected cells.

    In a primate model, the data were somewhat less promising. When macaques received topical cyclodextrin before being exposed to the virus, the treatment appeared to prevent infection initially, but offered little protection upon re-exposure to SIV, again following cyclodextrin prophylaxis.

    Hildreth said that may be because the animals received a massive dose of the virus -- "way more than you'd ever see in seminal fluid in a natural setting" -- and the batches of cyclodextrin used for the repeated doses were not of the same quality. He said he is now repeating the study using a "physiologically relevant" amount of the virus. "We're pretty confident."

    Hildreth explained that NPC is likely disrupting HIV transmission by affecting the trafficking of the viral protein Gag. "The very dramatic thing in NPC cells is the Gag protein seems to never make it to the plasma membrane."

    Currently, Hildreth is developing cyclodextrin as a microbicide against HIV. He has filed an investigational new drug application with the FDA, and is investigating whether the compound could serve as a therapeutic.

    Steven Walkley, who studies lysosomal storage disorders such as NPC at Albert Einstein College of Medicine in New York, said his own data show cyclodextrin has a "remarkable" effect on mice with NPC. "They're living literally twice as long as they would otherwise, " he said. "We were very surprised, to say the least." (He and his colleagues have submitted their findings for publication.)

    Walkley noted that his mice receive 4000 milligrams per kilogram of cyclodextrin -- 10 times a recent dose the Hempel girls received -- and he hasn't noticed any side effects. However, it's still unclear how exactly cyclodextrin is warding off NPC, which means there could be some side effects scientists have not yet discovered, he added. "Maybe there's something going on and we just haven't found it yet."

    Peter Pentchev, a retired scientist who worked with NPC for decades at the National Institutes of Health, echoed Walkley's opinion about the promise of cyclodextrin in NPC, dubbing it the "perfect drug" for the disease. He cautioned, though, that "we know what [cyclodextrin] does, but we don't know why or how." But scientists are working on those questions, he added. "In the next year, I'd be really surprised if we don't get some answers."

    Hempel, too, has failed to notice a single side effect since her girls began cyclodextrin infusions. "We're proving the safety of this compound," she said. "I definitely feel like Addi and Cassi are leading the way here, not only for NPC kids, but potentially for AIDS patients."

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