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MLV-Related Viruses - an explanation

Blog entry posted by Bob, Aug 27, 2010.

This blog relates to the paper published by the NIH/FDA in USA which found MLV-related viruses in 86% of ME patients, published on 23rd August 2010. http://www.pnas.org/content/early/2010/08/16/1006901107.full.pdf html

I've now also written a much briefer explanation of MLV-related viruses, which might also be helpful, here:
MLV related viruses - a simpler explanation http://www.forums.aboutmecfs.org/blog.php?b=518



Harvey J. Alter, one of the authors of the NIH/FDA paper, has said that many viruses which cause a single disease, such as Hep C and HIV, have multiple variants. Alter says that the variations of virus, found in CFS/ME patients both in his study and the WPI's Science paper, is exactly the pattern that he would expect from a human retrovirus.

In the published paper, Alter refers to three different types of virus that he detected in CFS patient blood samples, and there was also a fourth type in a blood donor sample. This is in addition to the XMRV detected in the Science paper.

Alter refers to these virus types specifically as 'CFS Type 1', 'CFS Type 2' and 'CFS Type 3'. It is not clear what Alter is exactly referring to by these terms (i.e. a type of CFS, a type of virus or a type of gene sequence?), but it seems that he is at least referring to the "viral gag gene sequences" that he was detecting.

Alter has very firmly stated that his study complements, validates, strengthens, and builds on the WPI's work, and it does not weaken the XMRV research in any way. The new study has brought to light a range of new virus types that are associated with ME/CFS. It is possible that these new variants might be found in even more ME patients than are currently testing positive for XMRV. At the moment, I think about half of the members of the Phoenix Rising forum (about 40%) are testing negative, and so it might end up that these patients test positive for these other variants in the future. I personally believe that this makes the collective future of ME patients even more hopeful.

So, in the case of ME/CFS, Alter seems to be saying that a group of viruses (or variants of a virus) are associated with a single disease, or syndrome. These viruses are all MLV-related viruses. There are a number of different strains, or varieties, or variants, or types (whatever you want to call them) of these MLV-related viruses.

MLVs (Murine Leukaemia Viruses) are mouse retroviruses that cause cancer in certain types of mice, whereas MLV-related viruses are human viruses which are closely related to MLVs. It seems that the MLV-related viruses are different enough from mouse viruses to be designated new human viruses, rather than mouse viruses.

In this published paper, all the variants which were discovered, except the ones detected in the blood donors, are all shown to be associated with ME/CFS. The possibility of multiple infections, with different MLV-related viruses, in an individual, may yet prove to contribute to increased severity of symptoms, or a wider range of symptoms. It might yet been shown that patients exhibit different symptoms relating to being infected by the different types of virus. The viruses might also be associated with other diseases, such as MS, Autism, Gulf War Syndrome and Lyme Disease. My understanding is that there is ongoing research looking into all of these diseases.

See here for a diagram, extracted from the Alter & Lo paper, of a 'phylogenetic tree' (i.e. a virus family tree) of MLV-related viruses and MLV's. Specifically, the diagram shows the relationship between the viral gag gene sequences detected in Alter's paper and XMRV's (XMRV variants) and MLV's:

http://www.cfids.org/mlv/phylogenetic-tree.pdf

The diagram shows the viral gag gene sequences detected in Alters paper (detected in blood samples of CFS patients and blood donors), labelled: CFS type 1, CFS type 2, CFS type 3, BD22, BD26, BD28.


All of Alters and Mikovits' viruses are MLV-related viruses. XMRV is one of these MLV-related viruses, as Judy Mikovits has always said. The Alter study, and Judy Mikovits, have now also confirmed that there are multiple variants of XMRV. The Alter paper specifically refers to "XMRVs" in the plural. There are also diagrams in the Alter paper showing how the XMRVs relate to the new polytropic MLV-related viruses.

Human Gamma Retroviruses (HGRV) seems to be the umbrella term for these MLV-related viruses. So far, the only known Human Gamma Retroviruses (HGRVs) are MLV-related viruses.
UPDATE: It has now been reported from the 1st international XMRV Conference that Judy Mikovits has suggested a new name: HMRV (Human MLV-related virus), which would encompass both Xenotropic and Polytropic MLV-Related Viruses.

The viruses, that Alter and Mikovits have published papers on, have all been designated as MLV-related-viruses. Alter seems to base his findings on virus gene sequences, rather than whole virus genomes.

Alter's viruses were previously unknown viruses, but similar to existing MLV's.
These viruses have mutated enough, since entering into the human population, such that they can be called new types of human viruses, and not mouse viruses.

These human retroviruses have now been found in a high percentage of ME/CFS patients in two published studies. (The Science paper, and now the PNAS paper).

XMRV:

XMRV is one type of these MLV-related viruses... It has now been confirmed that there are different variants, or types, of XMRV.

Here's what 'XMRV' stands for:
X - Xenotropic
M - Murine Leukaemia Virus (MLV)
R - related
V - retrovirus

So, as we can see from the 'M' (shortened from MLV) in XMRV, XMRV is related to Murine Leukaemia Viruses (MLV's), just the same as Alter's viruses are. XMRV was correctly classified as an MLV-related virus, the same as Alter's viruses. Throughout his paper, Alter refers to MLV-related viruses and MLV-like viruses.


Why Alter's viruses cannot be called 'XMRV':

A 'Xenotropic' virus cannot infect the species of origin (in this case, mice) with complete, replicating viruses but can infect another species (in this case, humans) with complete and replicating viruses.

A 'Polytropic' virus can infect both the original host species (i.e. mice) and another species (i.e. humans) with complete and replicating viruses.

The MLV-related virus sequences that Alter found most closely relate to 'Polytropic' MLV's, not 'Xenotropic' MLV's.

This means that they cannot be referred to as 'XMRV' because the 'X' (Xenotropic) does not apply to these viruses.
Instead, they are 'Polytropic-Murine Leukaemia Virus-Related Viruses' (So, I suppose he could have named them 'PMRV' instead of 'XMRV').

Alters MLV-related viruses are referred to as 'polytropic', because the MLV's which they related to can infect both the original host species (mice) and another species (humans) with whole and replicating viruses, whereas Xenotropic viruses cannot infect the species in which they originate (i.e. mice) with whole, replicating viruses, but can infect another species (i.e. humans) with whole and replicating viruses.
(Please see notes at the bottom of the page on the meaning of 'Xenotropic'.)

So, Alter's viruses are polytropic-MLV-related-viruses (the MLV's they are related to can infect mice with whole, replicating viruses), whereas XMRV is a xenotropic-MLV-related-virus (the MLV's it is related to cannot infect mice with whole, replicating viruses). The only difference in the terminology is the use of the words 'xenotropic' and 'polytropic', or a 'P' and an 'X'.

So, we have Alter's new P-MLV-related-viruses and Mikovits' X-MLV-related-viruses (XMRV). Both of these are 'MLV-related viruses', and they both fall under the informal umbrella terms Human MLV-related virus (HMRV) and 'Human Gamma Retroviruses' (HGRVs).
There are multiple varieties of both types of viruses. Alter has found CFS Type 1, CFS Type 2 and CFS Type 3 (although these terms seem to relate to gene sequences, rather than the actual viruses), and another, fourth type, in a blood donor sample.
Alter and Mikovits both seem to be saying that Judy Mikovits has also found multiple variants of Xenotropic-MLV-related viruses (XMRVs), and it has now been reported that Mikovits has also found Polytropic MLV-Related Viruses in some of the patient samples from her original Science paper.

Amy Dockser Marcus' Wall Street Journal blog says that Judy Mikovits has found polytropic type MLV-related viruses in some of the samples in her original Science study (so, along with XMRV, this means she is finding more than one MLV-related virus infection in individual samples), and I imagine that she is working furiously to find out the significance of this.

One other interesting thing to note is that the 'commentary' in PNAS says that:
So I believe that whether these new viruses are related to polytropic or xenotropic MLV's is not clear cut and is not particularly significant... it's just a case of wording, and possibly an unfortunate case of using an 'X' in the naming of XMRV.

Alter and Lo have only detected gene sequences for their polytropic MLV-related viruses, and have not sequenced the whole virus genome. So it might be possible that their 'polytropic MLV-related viruses' might also turn out to be hybrids of polytropic and xenotropic MLV's once their whole genome has been sequenced.

UPDATE: It looks like it might be more convenient, and appropriate, to use the name that Judy Mikovits has now suggested (at the 1st International XMRV conference): Human MLV-Related Virus (HMRV), which covers both 'X' and 'P' type MLV-Related Viruses.


Discussion about the meaning of 'Xenotropic':

Note that XMRV is an infectious human virus and is not, itself, a Xenotropic virus. It is only the MLV's (that XMRV relates to) which are referred to as Xenotropic, because of the behaviour of the viruses in mice.

A Xenotropic virus is not a complete, replicating virus in the original host species (i.e. mice), but can only become a whole, replicating virus once it jumps to another species.

It is not possible to infect the original host species with a Xenotropic virus because the host species has a genetic resistance to that virus such that the virus cannot exist as a complete and replicating virus in the host species.

So, a Xenotropic virus cannot infect the original host (e.g. mice) but can only infect another species (e.g. humans). It is only when a Xenotropic virus jumps to another species (e.g. to humans) that it is able to start replicating and forming whole, or complete, viruses, thus becoming an infectious exogenous virus.

Endogenous/Exogenous.
Exogenous viruses are what we typically think of as a virus. They are complete viruses which are transmitted via infection.

Endogenous viruses are hereditary sequences of the host species' DNA. They are passed from parent to offspring via reproduction. They are not stand-alone viruses. In humans, endogenous viruses are usually thought to be inactive and benign, although some still actively code for proteins. The DNA of an endogenous retrovirus is an integral part of the host species DNA, and endogenous viruses are transmitted from parent to offspring via the DNA of the germ lines cells (eggs and sperm), as an integral part of the species DNA.

My understanding is that a Xenotropic virus is always an endogenous retrovirus in the original host species. It would make sense if a Xenotropic virus was an endogenous virus in the original host species because endogenous viruses are an integral part of the host species' DNA and can exist in the host without forming whole, complete, replicating viruses. Host species are genetically resistant to their endogenous viruses. In the case of an endogenous Xenotropic virus, viral particles (partial viruses, viral RNA/DNA, or viral proteins) can jump to another species (e.g. to humans) where they become active and able to form whole, or complete, viruses and start replicating, thus becoming an infectious exogenous retrovirus in the new species. The original host species (e.g. mice) would be genetically immune to being infected by whole, replicating viruses, even though they harbour the virus particles that can cause a full infection of another species.

Benign?
Some definitions of 'Xenotropic' state that a Xenotropic virus is 'benign' in the original host species. A question that has been raised is, if Xenotropic viruses are, by definition, 'benign' in the host species, then why are MLV's referred to as 'Xenotropic', when they are known to cause cancer in certain types of mice (so they are clearly not benign)? This question is explored in the discussion after this blog.
I wonder if it is more accurate to say that Xenotropic viruses are non-infectious, and non-replicating in the original host species, rather than entirely 'benign'. I can see why there could be confusion here as endogenous retroviruses, for example, are usually thought to be benign, but in certain circumstances they might not be (i.e. wild mice are vulnerable to infection from certain endogenous retroviruses in bred mice.) In humans, endogenous retroviruses are generally thought to be benign, but they are being investigated for possible association with diseases such as schizophrenia. Prof Huber is researching the human endogenous retroviruses, HERV-K18, for a possible association with ME/CFS.

XMRV:
It is thought that XMRV originated as a mouse virus (an MLV) which jumped species and then mutated in the human population (or before it reached the human population if another species was also involved), such that it is no longer an MLV (it is not genetically identical to any known MLV's).
XMRV has 'Xenotropic' in its name because it is closely related to a Xenotropic mouse virus, not because it is actually a Xenotropic virus. XMRV is an exogenous human retrovirus, not a Xenotropic MLV.
I imagine that mice still have a resistance to XMRV and so cannot be infected with it, but I'm not clear about this. If the virus mutates enough, then mice could lose their resistance to it.
XMRV is a human retrovirus but it is not a xenotropic human virus... it is a [Xenotropic mouse virus]-related virus.


A Question regarding MLV research:
I do have a question that doesn't seem to be answered... If we know that polytropic and xenotropic mouse retroviruses exist, then why hasn't there been more studies done on these viruses before? Polytropic and Xenotropic viruses, by definition, can infect other species (i.e. humans), so why have these MLVs only been investigated in humans recently?


Notes:

It's important to keep in mind that Alter's study is based on the detection of gene sequences from the viruses, rather than whole virus genomes.

MLV's are also known as MuLV's.
Some types of MLV's are also known as mERV's (mouse endogenous retroviruses), but not all MLV's are endogenous.

Alter checked all of his blood samples for contamination with mouse DNA, which showed negative for all mouse DNA.
This proves that there is also no contamination from endogenous mouse viruses, but I believe that this method does not prove that there is no contamination from exogenous mouse viruses. The variability of the MLV-related viruses found, along with other safeguards in the study, satisfied the journal PNAS that there was no contamination with MLV's.

.
  1. alex3619
    Hi, just a few comments. First, we know that XMRV can be found in Macaques because we put it there - I doubt anybody has done a survey of primates around the world. It is true though that it has not yet been found naturally in other species.

    XMRV did not mutate to be unable to infect mice. Mice mutated to be unable to be infected by viruses using the Xpr1 receptor. What would cause such a mutation? Massive death rates, or a massive decline in fertility when infected. Bye, Alex
  2. Bob
    Hi Marly,
    Thanks for sharing your thoughts... very interesting... There's just so many questions at this stage, aren't there! And not so many answers.
    Your understanding about the subject seems to equal my non-scientist understanding, but there is one small point that, for clarity, I'd like to mention... Although, from what you've written, you clearly know this already, but I just thought I'd mention it for clarity... I think that XMRV is not "within the family of MLV's", because, as you say, XMRV is a human virus and MLV's are mouse viruses... So, XMRV is very similar to MLV's but it is not an MLV... (i.e. XMRV is not a mouse virus so it cannot be an MLV, but it's an MLV-related virus)... If XMRV also turns out to be a mouse virus (it hasn't been found in mice yet), then yes, maybe it would then be "within the family of MLV's". (But I'm not certain about this last detail!) It's all extremely confusing!

    Bob
  3. PANDORA
    Bob, Cort and others, you'all understand this process and the jargon much better than I do indeed. I always enjoy reading the reports from individuals like you.

    The science behind XMRV is indeed complicated and for me as a lay person with CFS-ME gets even worse. But this is what I understood it to be in very simple terms:
    XMRV is found in human only. XMRV according to DR. Mikovits is a retrovirus within the family of MLV's which have already jumped so to speak to humans, (they have different gene sequencing) and leading to the comment by Dr. Mikovits during the NJCFSA presentation that what the Alter/FDA paper found is actually XMRV, but these researchers perhaps because of the technique or lack of sensitivity to find the virus XMRV could not detect it, but the mere fact that they found MLV's is exciting and leads to the potential and strong hypothesis (conclusion) that if the FDA/Alter/NIH researcher found MLV's then XMRV can certainly be found too if the correct technique for detection is applied.

    Contamination issue and if I understood correctly: According to Dr. Mikovits, since XMRV is a human retrovirus, it cannot be found in mice. The contamination issue has been reported in labs that work with the mouse retrovirus and there is why the contamination has occurred. WPI labs do not work with the mouse virus only with the human type XMRV.

    In theory, even though the NIH/FDA/Alter paper did not acknowledge finding XMRV, they did find other traces of MLV leading then to the conclusion that they are in the right track and more study needs to be conducted.

    The two most difficult questions that WPI/Mikovits are working hard to answer are: 1) How XMRV pushes a CFS patient into the threshold of CFS-ME (immune dysfunction level that makes the patient very sick or chronically ill)? 2) How to find a treatment to stop this process?

    Amazingly they are working successfully towards these two awesome goals. If they answer question number one: XMRV will show to cause CFS or have such a strong relationship (and they will be a able to prove it scientifically) that leads to being the cause. Just like in AIDS, people don't die of HIV, they die of the co-infections or co-morbidity that envelops and destroy their immune system, one that is so compromised that cannot react as it should. Dr. Mikovits said that the hypothesis is that if XMRV pushes the immune system to the threshold of CFS-ME, (It is a simple retrovirus it also has the same damaging characteristic of its cousin HIV. ), then we will have found the cause of ME-CFS.

    Another important questions that they need to answer are: Do all CFS-ME patients have XMRV? Will there be tests that will be able to identify the process of getting sick with CFS-ME? If so, can we prevent it? Just like in AIDS, many are positive for HIV and not be sick with AIDS. The process for CFS-ME detection and diagnosis seems to going in the same route. No wonder we all worry about our spouses, children, family members and of course the blood supply.

    The discovery of XMRV has shaken the foundation of the well-known nay-sayers within the scientific community. Additional and constant pressure by the patient advocacy community needs to remain high at all times. We cannot let the fiasco of the late 80's and mid 90's occur again. We, as patients and or family members of CFS-ME patients are now strong as ever and we need to seize the moment. I believe there has been a huge shift within the NIH already. I heard it. I saw it and I believe that as long as we keep the pressure (we cannot let our vigilance go out of site), it will be a huge step towards a solution for our patient community. Soon it will be one within the CDC too. They have no choice. The Time is Now.
    Thank you for all that you do.
    Marly
  4. Cort
    Actually these viruses have been very well studied - which just goes to show how much money is available for medical research. The fact that they are retroviruses and can cause cancer in animals has apparently been enough for the research community to do alot of work on them. In fact our own Sandra Ruscetti has done alot of work on them.

    Its our amazing luck that Dr. Mikovits just happend to be close to a researcher who spent much of her career studying these viruses! PubMed lists 100 publications by Sandra Ruscetti on these or associated topics.

    Here's are a few

    Neurodegeneration induced by PVC-211 murine leukemia virus is associated with increased levels of vascular endothelial growth factor and macrophage inflammatory protein 1 alpha and is inhibited by blocking activation of microglia.
    Li X, Hanson C, Cmarik JL, Ruscetti S.
    J Virol. 2009 May;83(10):4912-22. Epub 2009 Mar 11.

    A unique heparin-binding domain in the envelope protein of the neuropathogenic PVC-211 murine leukemia virus may contribute to its brain capillary endothelial cell tropism.
    Jinno-Oue A, Oue M, Ruscetti SK.
    J Virol. 2001 Dec;75(24):12439-45.

    10.Analysis of the disease potential of a recombinant retrovirus containing Friend murine leukemia virus sequences and a unique long terminal repeat from feline leukemia virus.
    Nishigaki K, Hanson C, Thompson D, Yugawa T, Hisasue M, Tsujimoto H, Ruscetti S.
    J Virol. 2002 Feb;76(3):1527-32.PMID: 11773427 [PubMed - indexed for MEDLINE]Free PMC ArticleFree text
  5. Bob
    anciendaze and Rusty... thanks very much for the feedback... it's really appreciated.
  6. Bob
    I think that the main point is that these Xenotropic MLV's cannot infect, become whole, or replicate in, mice. They only exist as strands of the mouse DNA and not as separate, whole, viruses. If they cause harm in mice, then there are probably certain harmful protein strands that are being made by the retrovirus DNA, a big like Huber says a HERV-K18 (human retrovirus) gene, can cause a 'superantigen' to be made, but human retroviruses are generally thought to be harmless. I think that, by definition, retroviruses are generally thought to be benign (harmless), otherwise the whole species would die out. I think that we may have been focusing on the 'harmless' part of the definition too much, whereas the rest of the definition of xenotropic is more relevant.
  7. dschlindwein
    Maybe you're right, but we are then owed an explanation of [Xenotropic MLV], which, as both of us have noted, is self-contradictory unless the MLVs in question do not cause cancer in mice. I'm going for {Xenotropic [MLV]-related virus}, where the MLV's becoming xenotropic is why "-related virus" was appended simultaneously with its being designated as "Xenotropic." You are saying instead that "-related virus" refers to the mutations that have occurred, causing XMRV not to be found in mice, which would also be a good reason to append the "-related virus" phrase. Maybe they should have called it XMRVRV. Or XMLVRVRV, for clarity. Clarity? Let's have a round of applause for HGRV!
  8. Bob
    Hi, yes, it's been fun and fruitless! My brain is exhausted today as well!
    I'm going for a {Xenotropic-MLV} that has mutated to become a {[Xenotropic-MLV]-related virus}
  9. dschlindwein
    After I posted my most recent reply I saw your thoughtful response to my earlier two questions. I think we are both converging on "mutated {Xenotropic [MLV-related virus]}." But we are not the ones who named the thing! So much to learn, and so little mental energy. My brain got a workout today, and I expect I'll be paying the price for the next few days. But it was fun, if maybe fruitless. Almost reminds me of days gone by when I was in academia, solving grammatical puzzles that were often based on faulty data and therefore their "solutions" something less than meaningful.
  10. Bob
    Oh, I love how the brackets are getting so complex now! {[(<->)]} lol
    Yes, it has me stumped too... How can an MLV (causes cancer) be Xenotropic (harmless)?
    Maybe this is related to MLV's only causing cancer in 'certain' mice.
    Maybe MLV's are harmless in a majority of mice? And so maybe the word has been used sloppily in relation to XMRV? I don't know.
    Ah, I've just thought... although these MLV's might cause cancer in 'certain' mice, maybe they still do not form complete, replicating viruses in these mice, and so the term xenotropic is correct in every detail except the fact that it does cause harm in some mice.
    So the difference between a polytropic mouse virus and a xenotropic mouse virus, in this case, would be that the polytropic MLV's can infect and replicate in mice, whereas the xenotropic viruses cannot infect and replicate in mice. I think that must be the answer, but I stand to be corrected.
    I think that endogenous retroviruses are generally thought to be harmless because they are a part of the DNA of the species, so if they were harmful then the species would die out. I think it must be a case of sloppy terminology.