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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.

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  1. dschlindwein
    Would another possibility be that what the WPI found is a mutated {Xenotropic [MLV-related virus]}, which because of its mutations can no longer infect mice? I suggest this because the [Xenotropic MLV] part of [Xenotropic MLV]-related virus still doesn't make sense to me. Why would an MLV's jumping species (i.e. becoming xenotropic) suddenly render it harmless in mice, which is what the definition of xenotropic seems to require? Unless MLVs are found benignly in mice, in which case the MLV designation is what is causing me my problems in understanding.
  2. Bob
    Hi dschlindwein, thanks for your comments. You ask a good question, and I'm just as confused as you are! And don't worry, you can't help but ask a 'contorted' question with this confusing subject! I'll try to answer to the best of my knowledge, but I'm not an expert on this subject.

    So here goes with my contorted answer (takes a deep breath): I have always thought that XMRV stood for Xenotropic-[MLV-related virus] (meaning that i thought XMRV is xenotropic), but now i think that is wrong, and that it is a [Xenotropic-MLV]-related virus (where XMRV is not xenotropic itself, but is related to a xenotropic MLV virus). The reason for this is that XMRV is supposed to be closely related to Xenotropic-MLV's. Also, XMRV is not a Xenotropic mouse virus because is not found in mice (I think I am correct here), so it is a human virus. And XMRV cannot be a Xenotropic human virus, because it is a harmful human retrovirus, and has not jumped species from humans, as far as we are aware. I was learning all this as I wrote this blog, so I might not have expressed some parts of it so clearly. I only really cleared it up for myself when I investigated the exact meaning of 'Xenotropic', as I discussed at the end of the blog. I may also have confused the situation with the bad use of my brackets (). XMRV is not a mouse virus, and the DNA/RNA of XMRV cannot be found in mice (I think I'm correct here).

    So this is possibly what happened in the history of XMRV: First it started out as a Xenotropic endogenous mouse retrovirus (endogenous retrovirus = written into the mouse DNA). This virus would have been harmless to the mouse, and could not form a whole, active, virus. (Xenotropic = harmless to mouse but can infect another species). So the mouse jumped species - maybe directly to humans, but maybe via another species. Then the virus mutated so that it was no longer the same as the virus which was written into the mouse DNA. At this point (after it has mutated), the virus is no longer a mouse virus, but it is a human virus. As a human virus, it is no longer a Xenotropic mouse virus.
    Please ask if that doesn't make any sense (it probably doesn't!).

    Your interpretation of a Xenotropic-(MLV-related virus) looks absolutely correct to me. And you have brought up another interesting question... Surely a 'Xenotropic MLV' is an oxymoron? Because Xenotropic viruses are harmless to the host (a mouse), but MLV's cause cancer in certain mice, therefore they are not harmless. So how can we have a harmless virus that causes cancer? My brain has just imploded!

    Another thing that I've just read is that XMRV has genes which are a hybrid of polytropic and xenotropic MLV's. So it is possible that XMRV is a result of polytropic and xenotropic MLV's combining together.
  3. dschlindwein
    Second try: You are clear at the end of your post about XMRV not actually being Xenotropic. Therefore [Xenotropic Murine Leukemia Virus]-related virus. So, does this mean that humans picked up an MLV (which therefore became a Xenotropic Murine Leukemia Virus) and it may have been harmless to humans until it eventually mutated in humans into something related to that Xenotropic Murine Leukemia Virus, namely, the [Xenotropic Murine Leukemia Virus]-related virus? Thanks. I guess this must be what you are saying, since you do tell us that XMRV DNA is not found in mice. Please understand that I am trying to understand, and am not intending anything else with my contorted question.
  4. dschlindwein
    Thank you, Bob, for delving into the PNAS publication and explaining how it complements and reinforces the WPI's findings. I'm somewhat confused, though, (not your fault, I'm sure, it's just my dysfunctional brain): What is the "scope" (as we use the term in linguistics) of the terms Xenotropic and Polytropic in what are soon to be known as HGRVs? Is it [Xenotropic Murine Leukemia Virus]-related virus, as you say at the bottom of your post, or is it Xenotropic [Murine Leukemia Virus-related virus], which is what I thought I understood in the body of your post? I am not trying to be cute. I am just confused. I think I can get a grasp of the meaning of Xenotropic [Murine Leukemia Virus-related virus]; some mice have a harmless (to them) endogenous virus related to another murine virus, a leukemia-causing MLV, and the harmless (to mice) virus has jumped species to humans, in whom it is exogenous and not harmless. I can't, however, get my dull mind around [Xenotropic Murine Leukemia Virus]-related virus, though there may very well be a sensible interpretation. Thanks again for the excellent post.
  5. RustyJ
    Bob, very comprehensible article, although I may have to read it 30 times to get the info to stick. Then start all over again tomorrow.

    It is good to see the basics reiterated, particularly for us Goldfish-variant CFSers (new variant?)

    A good effort to explain the science. Really focuses down onto the critical questions and steers clear of emotion-laden inferences - well done.

    What you have done is gotten on with the job and written your own article to show it can be done, despite the limitations of your illness.

    I hope we can get some constructive debate of the facts here.
  6. anciendaze
    Excellent summary of a highly-technical topic. I'm assuming you have background training. This is beyond what I would expect of a civilian reporter, including Cort, who took unwarranted heat for errors in his coverage.

    (OK people, if you expect coverage comparable to a researcher or Pullitzer-prize winner, why don't you pay him at that rate?)

    The revealed variability changes some preliminary conclusions based on apparent lower variability. This bug has been around for a while. Where? In what species? When did it reach humans?

    I think the outbreaks in 1985 cannot be the original ones for these strains.