Thursday, November 26, 2009

The Modus Operandi of XMRV: Pt1

In a 2 part series I will explain the mechanisms by which XMRV enters human cells, and possible consequences.  The cell surface receptors for XMRV have been identified as XPR1 and SYG1: XPR1 is G-protein coupled receptor suspected as a putative progesterone receptor.  The first part I will deal with deals with XPR1.

XPR1 is a membrane protein which acts as a signal transducer: it crosses the plasma membrane 7 times.  Recently, the structures of a handful of G-protein coupled receptors has been elucidated: Rhodopsin - a visual protein, Beta-adregenic receptor - adrenaline receptor and target for beta blockers, and the A2A adenosine receptor - the receptor our favorite wake up drug caffeine binds to.  XPR1 is found in a fairly diverse array of tissues: lymphocytes, hepatocytes, as well as cells in the brain, pancreas, kidney, prostate, and muscle.  This is a very important finding indeed.

It is of note that progesterone tends to shift the immune balance towards Th2, and that progesterone levels rise to as much as 10 to 15 times normal during the third trimester.  So, as a molecular biologist, it leaves me to theorize that if this virus can mimic progesterone, it can create a state that allows the immune system to ignore the virus, very much like it ignores a developing fetus - scary isn't it?  It is also worth noting that mutations in XPR1 bear a strong association with miscarriage, and that such women often bear masculine-like features.  Observations reveal that high rates of estrogen, or high rates of testosterone in the absence of progesterone tend to favor the growth of XMRV - progesterone inhibits the formation of DHT.  It seems to indicate that succeptibility to ME/CFS is strongly hormone driven, and why ME/CFS and FM are strongly female prevalent.

J. Battini, J.E. Rasko, D. Miller. (1998).  A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: Possible role in G protein-coupled signal transduction.  Proceedings of the National Academy of Sciences:


  1. This comment is a general question, not directly related to this post.
    Assuming that XMRV is proven to be the puppetmaster behind CFS, and assuming that there is a link found between XMRV and autism, what would account for the disparity in the symptoms? Why don't autistic children or adults suffer from fatigue (or do they?). Could the age at which a person experiences the complete immune collapse be the key factor? infancy = autism; early childhood = ???; young adulthood onward = CFS?

    By the way, your blog is outstanding. Thank you.

  2. To anonymous: I cannot speak for other autistic children, but my son is definitely feeling very fatigued a lot of the time (he is verbal and able to express). Considering the mitochondrial dysfunction markers in autism, it wouldn't be surprising at all if fatigue was very common.

  3. Have I got this right: low progesterone encourages XMRV which then makes its own progesterone to suppress the immune system? Would the progesterone 'produced' by XMRV show up in a hormone test - or just the background levels of 'real' progesterone? Thanks.

  4. This strikes a chord with me. ME for decades (acute viral start). Low progesterone on testing. Masculine features (blush). Many failed IVF cycles. Lots of progesterone injections = worsening of health.

    XMRV testing planned (and on VIP waiting list for kit)

  5. This is very interesting - what are the implications for women with ME/CFS who may have XMRV and are on HRT with both estrogen & progestogen? Is one or the other or both best avoided?

    Terrific blog, keep it up!

  6. Fascinating blog.
    There are reports that pregnant women experience an improvement of CFS symptoms. How does this fit into your model?

  7. I think progesterone actually has a protective effect, by acting as a cell entry inhibitor. XMRV competes with the membrane bound progesterone receptor, as opposed to the classic nuclear binding cytoplasmic receptor.

  8. I really want to understand what you are saying, though I lack much scientific background. Could you please translate these findings and your hypotheses coming out of them as well as possible? Are you suggesting that actual progesterone inhibits XMRV? Also, what is DHT?

    I quote you: "Observations reveal that high rates of estrogen, or high rates of testosterone in the absence of progesterone tend to favor the growth of XMRV - progesterone inhibits the formation of DHT."

    In terms of suggestions, what would you suggest, hypothetically, as the best or worst hormonal environment for the spread of XMRV?

  9. i am xmrv positive. have been debilitated w/"cfid's" for 5+ years... bed-bound fatigue = worst symptom.

    prior to illness, i was unable to conceive naturally. (stage 4 endometriosis)..went thru one ivf cycle: conceived and gave birth to a healthy son. felt fine thru-out pregnancy.

    when son was 2.5 years old, i drugged up for 2nd was after this cycle of ivf drugs that i became ill.

    during this same time period developed an abcessed tooth and had multiple rc's, extractions and debridements.....tied my illness to jaw infection.

    after reading this post seems like the ivf drugs may have played a large role in activating the sleeping beast...xmrv?!?!?!

    thanks for the fabulous make the extremely complex much easier to understand for us lay people : )


  10. I have a boyish build, both my daughters and myself have had hell with hormones. Contraceptive pill has been a complete no go.

    Both my daughters are tall and curvy.

    I think I am a fragile X carrier genetic markers are FMR1 & NUFIP2. I also have the simian line.

    Also my youngest daughter is autistic, and my paternal grandmother had A-typical MS.

    can anyone shed any light on any links between Fragile-X and XMRV. Or XMRV and FMR1 & NUFIP2

    ThanQ for your help.

  11. As a CFS patient it feels to me as if the immune response is abused in inflammatory hotspots.
    Aspirin seems to help.

    When there is no infection the virus can spread without any symptoms.
    The pH measure rises then. Now as soon as there is some kind of infection symptoms of that infection occur ... oxygen, additional energy (heat) and hormones are required.

    EBV is an opportunistic desease in such an environment. But it needs to be fueled with hormones.
    Most hormones will do. I get sick when I should feel happy. Sleep probably helps with the pH measure but the situation in the inflammatory hotspots gets worse.

    Might it feel like that according to this articles assumptions?

  12. Is there anything someone who has had CFS can do to help ensure a healthy pregnancy?

  13. J Virol. 2009 Nov 11. [Epub ahead of print]
    Androgen Stimulates Transcription and Replication of XMRV (Xenotropic Murine Leukemia Virus-Related Virus).

    Dong B, Silverman RH.

    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195.

    XMRV is a gammaretrovirus originally identified in a subset of prostate cancer patients. Because androgens stimulate prostate tumors and some retroviruses, we investigated effects of dihydrotestosterone (DHT) on XMRV transcription and replication. Transcription from the XMRV U3 region was stimulated up to 2-fold by DHT, but only in cells containing a functional androgen receptor. Mutations in the glucocorticoid response element (GRE) of XMRV impaired basal transcription and androgen responsiveness. Furthermore, DHT stimulated XMRV replication by 3-fold, whereas androgen inhibitors (casodex and flutamide) suppressed viral growth up to 3-fold. Findings suggest that integration of the XMRV LTR into host DNA could impart androgen stimulation on cellular genes.

    Jose Luis from Spain!

  14. Four important points:
    1.XPR1 and SYG1 are two names for the same protein, which is the receptor for xenotropic retroviruses
    2. the exact number of times XPR1 crosses the membrane has not been determined, but best estimates are 8-9 and not 7. It is definitely not a traditional seven-spanner G-coupled receptor.
    3. There is no evidence XPR1 binds to G proteins. The data for yeast Syg1 binding to yeast G is also suspect. Only a truncated protein bound Galpha, the intact yeast XPR1-like receptor protein did not bind Galpha. No one has shown that XPR1 receptor binds to Galpha.
    4. XPR1 has a large "PHO" domain that is found in yeast and plant proteins that regulate phosphate uptake and metabolism. But XPR1 does not transport inorganic phosphate. At present, its function is unknown.

  15. Q to Anonymous:

    any indications on whether XPR1/SYG1 is linked to or interacts in any direct way with either NMDAs or voltage gated calcium channels? Has anyone been looking into that?

    Many thanks in advance

  16. Please note that there is no evidence that Xpr1, the cell-entry receptor for XMRV, is a progesterone receptor. This incorrect conclusion stems from the unfortunate use of the term "Xpr-1" as an abbreviation for the Xenopus Progesterone Receptor-1, which has no relationship to the XMRV receptor, Xpr1. It appears the abbreviation for the Xenopus protein has now been changed to PrgA (progesterone receptor A).

    Tian,J., Kim,S., Heilig,E. and Ruderman,J.V., Identification of XPR-1, a progesterone receptor required for Xenopus oocyte activation, Proc. Natl. Acad. Sci. U.S.A. 97:14358-14363 (2000)