MLV-Related Viruses

by Bob Courtney

The following article was submitted to Invest in ME by Bob Courtney and concerns the MLV-related viruses now under discussion following the research performed by the Whittemore-Peterson Institute, National Cancer Institute and the Cleveland Clinic.

August 2010

The recent paper published by the NIH/FDA in USA, which supports the research findings of WPI/NCI/CC was authored by Harvey Alter et al.

OK, I've read the paper now, and so, in case anyone still has any confusion relating to the MLV-related viruses that Alter found... I might be able to bring some clarity to the situation... or probably not... but I’ll have a go anyway...

Harvey J. Alter, one of the authors of the paper, says that many viruses which cause a single disease, such as Hep C and HIV, have multiple variants, or types. He specifically said that Hep C has a quite a few different variants. So, he is saying that, what they have found in CFS/ME, is exactly what 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.

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. does he mean a type of CFS, type of virus or type of gene sequence?), but it seems that he is at least referring to the "viral gag gene sequences" that he was detecting.

This study strengthens the WPI's work, and it does not weaken it in any way. It has brought to light a range of new virus types that are associated with ME/CFS. And it means that these retroviruses might be found in even more of us than are currently testing positive for XMRV. At the moment, I think about half of the members of this forum are testing negative, and so it might end up that they test positive for these other variants in the future. I believe that this makes our collective future even more hopeful.

So, in the case of ME/CFS, Alter seems to be saying that a group of viruses (or variants of virus) are associated with a single disease, or syndrome... These viruses are all MLV-related viruses (murine leukaemia virus - related viruses), and they are also all Human Gamma Retroviruses (HGRV)... They have a number of different strains, or varieties, or variants, or types (whatever you want to call them). In this published paper, all the variants which were discovered, except the one discovered in the blood donor, are all shown to be associated with a single disease, known as ME/CFS, or you could say that they are all associated with a 'syndrome' (CFS is a syndrome), where the patients may yet be shown to exhibit different symptoms within that syndrome, possibly 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, Lyme Disease... and there is ongoing research looking into all of these. The possibility of multiple infections, of different MLV-related viruses, in an individual, might also contribute to increased, or a wider range of, symptoms.

Alter has very firmly stated that his study complements, confirms and broadens the WPI's research, and does not detract from it in any way.

So, it seems that they have discovered Human Gamma Retroviruses (HGRV's) in people with ME. ('HGRV' seems to be the umbrella term for these MLV-related human gamma retroviruses). XMRV is one of these HGRV's, as Judy Mikovits has always said. The Alter study, and Judy Mikovits, have also confirmed that there are also different types of XMRV. This paper specifically refers to "XMRVs" in the plural. There are also diagrams in the paper showing how the XMRVs relate to the other, new, MLV-related viruses.

See here for a diagram, extracted from the Alter & Lo paper, of a phylogenetic tree of MLV-related virus gag gene sequences taken from blood samples of CFS patients and blood donors, and how they related to MLV's:


All the Human Gamma Retroviruses (HGRV’s) found, so far, are all MLV-related viruses (MLV = murine leukaemia virus) (Note that MLV’s are mouse retroviruses that cause cancer in certain types of mice.) 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. I suppose that if a mouse virus, or mouse related virus is found in the human population, then these newly discovered human viruses need to be designated as human viruses, rather than mouse viruses.

I'm not sure, from the wording of the paper, how much similarity there is between the mouse viruses and the human viruses.
i.e. were all of Alter's viruses were previously unknown viruses, but similar to existing MLV's? or are they identical to existing MLVs? Have these viruses mutated enough, since being in the mice population, such that they can be called new viruses?

Alter checked all of his blood samples for contamination with mouse DNA, which showed negative for all mouse DNA, which suggests that all these viruses have mutated and are not identical to any mouse retroviruses, therefore they can be called new viruses.

HGRV's (specifically MLV-related viruses) 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 (and so it's also an HGRV)... 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 you 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); it can only infect other species (in this case, humans.)
It is important to note that the HGRVs, or MLV-related viruses, that Alter found could not be designated as being 'Xenotropic' type, or related to Xenotropic type viruses.

The MLV-related viruses 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').
Alter’s MLV-related viruses are referred to as 'polytropic', because the MLV's which they related to can infect both the host species (mice) and another species (humans), whereas Xenotropic viruses cannot infect the species in which they originate (i.e. mice), but can infect another species (i.e. humans).
(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), whereas XMRV is a xenotropic-MLV-related-virus (the MLV's it is related to cannot infect mice). 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 Mikovit's x-MLV-related-viruses (XMRV). Both of these are 'MLV-related viruses', and they both fall under the umbrella term '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 might relate to gene sequences, rather than the actual viruses – it’s not clear), and another, fourth type, in a blood donor sample.
And Alter and Mikovits both seem to be saying that Judy Mikovits has also found multiple variants of her xenotropic-MLV-related viruses (XMRVs).
All of these MLV-related viruses, are HGRV's, so they all fit under the newly designated name Human Gamma Retrovirus HGRV. (Or, at least, is has been reported that HGRV is the new umbrella name for these viruses.)

And now 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.
 

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.


A note about the meaning of 'Xenotropic':

Note that XMRV itself is an infectious human virus, and therefore it is not a Xenotropic virus, but the MLV's that it relates to are Xenotropic.

This question is explored in the discussion after my blog entry:
http://www.forums.aboutmecfs.org/blog.php?b=515


XMRV:
I don't think that XMRV has been found, genetically, in mice, which is why it is called an MLV-related virus, and not an MLV.

Alter checked all of his blood samples for contamination with mouse DNA, which showed negative for all mouse DNA, which suggests that all these viruses have mutated since being in the mouse species, and they are not identical to any mouse retroviruses, so I imagine that the same was done for the XMRV studies.

This means that the origins of XMRV are a mouse virus, but that it has 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.

XMRV has 'Xenotropic' in its name because it is closely related to a Xenotropic mouse virus, not because it is actually a Xenotropic virus. It is an exogenous human retrovirus, not a Xenotropic MLV.

So, XMRV has its origins in mice, and it has mutated in humans enough so that the XMRV virus DNA cannot be found in mouse DNA.
I imagine that mice still have a resistance to it and so cannot be infected with it, but I'm not clear about this. If the virus mutated enough, then mice could lose their resistance to it.
XMRV DNA is not found in mice and therefore it is not actually a Xenotropic mouse virus (and it's not a Xenotropic human virus) but it is a (Xenotropic mouse virus)-related virus, and a human retrovirus, which is exactly how it has been designated.

A question:
I do have a question that doesn't seem to be answered... If we know that polytropic and xenotropic mouse retroviruses exist, then why haven'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 recently? Or have we only just discovered that there are Xenotropic and Polytropic MLV's?
 

Submitted to Invest in ME by Bob Courtney - August 2010