MLV-related viruses - an explanation
UPDATE: I've now written a much shorter and simpler 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.
There were three different MLV-related retroviral gag gene sequences identified by PCR in the blood samples of the CFS patients and a fourth variant was detected in blood donor BD22.
The sequence of all four variants were more closely related to the sequence of polytropic mouse endogenous retroviruses (mERV's) than to those of XMRVs.
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.
Although variations were observed, the majority (18/21, 86%) of CFS patient samples had the same viral gag gene sequence (CFS type 1) , whereas 2/21 had a different, but similar, viral gag gene sequence (CFS type 2), and a third distinct sequence (CFS type 3) was found in the remaining CFS case.
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.
MLV’s (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 MLV’s. 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 Alter’s 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 Alter’s 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 (HGRV’s) 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.
The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs...
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 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.
But in the months since then, they have continued to study the CFS patients included in the Science paper and Mikovits says that almost all of them are positive for one or more MLV-related viruses, including X and P.
http://blogs.wsj.com/health/2010/08...is-mark-the-spot-in-chronic-fatigue-syndrome/
One other interesting thing to note is that the 'commentary' in PNAS says that:
...XMRV genomes are actually hybrids between polytropic endogenous MLV sequences ... and xenotropic MLV ...
http://www.pnas.org/content/early/2010/08/16/1007944107
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.
xenotropic /xeno•tro•pic/ (zen″o-tropik) pertaining to a virus that is found benignly in cells of one animal species but that will replicate into complete virus particles only when it infects cells of a different species.
Xenotropic (Science: virology) refers to a genetically transmitted retrovirus that cannot replicate in the host species that is harboring it but which can infect and can only replicate in the cells of a different species.
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 my blog entry.
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.
