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XMRV - Human Virus or Mouse Virus? Technical Explanation.

Blog entry posted by Bob, Oct 22, 2010.

I can't guarantee that this blog is 100% accurate because I'm not an expert in mouse virology! But I think it's all accurate, after having done some heavy-duty reading about it all. This is purely a discussion of my understanding of the subject, as a lay person.
Any comments or corrections are welcome.

Update: I made an error in this blog regarding the behaviour, and method of transmission, of X-MLV's in X-MLV resistant mice. Thanks to Dr Yes for pointing out that whole X-MLV's are formed in X-MLV resistant mice, whereas I had thought that only partial viruses, or viral particles, could form in this type of mouse. Please see Dr Yes's post in the discussion thread, below, for the correction and some further useful clarifications.
I have corrected the blog and added some clarifications, extra info, additional notes and my sources, and it is now accurate to my best knowledge, with some further clarification from Dr Yes in his post below.
Apologies for the incorrect information. I had warned that there may be inaccuracies, because I'm a lay person (ME patient) and not an expert in mouse virology, but apologies anyway.
The reason for my confusion is that I had thought endogenous viruses could not form whole, fully active, viruses in the host species, but it seems that this is not (always) the case. No human endogenous viruses form whole viruses.


XMRV is purely a human virus, as per as our current knowledge, and it has never been found in mice, so far.
The confusion about whether XMRV is a mouse virus or a human virus arises because XMRV is very similar to MLV's, which are mouse retroviruses.
The similarity to MLV's is where the name comes from:

X - Xenotropic
M - MLV
R - Related
V - Virus

So, XMRV is an MLV-related virus. This means that XMRV is related to MLV's but it is not an MLV itself because MLV's are mouse viruses, whereas XMRV is a human virus... A new human retrovirus.

Another reason for some of the confusion is the use of the 'X' or 'Xenotropic'.

The 'X' ('xenotropic') in 'XMRV' refers to the behaviour of MLV's and indicates that a virus can infect, and replicate in, the cells of a species (e.g. in this case, humans) other than the original host species (e.g. in this case, mice), but that it cannot infect the cells of the original host species (mice). Actually, since the naming of these xenotropic viruses, it has been discovered that the Xenotropic virus behaviour only applies to certain strains of mice, and that some mice have cells that are susceptible to infection by these viruses (more on this below.)

In the case of XMRV, the 'X' ('xenotropic') is referring to the name of the mouse viruses (X-type MLV's) that XMRV is similar to... The 'X' is not referring directly to the behaviour of the new human virus 'XMRV'.
So, in other words, the X-type MLV's, that XMRV is similar to, can infect other species other than the original mouse host, but they cannot infect the cells of the strains of mice that the 'Xenotropic' name applies to (other strains of mice do have cells that can be infected.)

So a question arises: "How can a mouse virus exist in these mice the first place if it cannot infect the cells of the mouse host?"
This is where it gets even more confusing!
'X' type MLV's (Xenotropic MLV's) are 'endogenous' retroviruses. An endogenous virus is not an independent virus, but exists as an integral part of the host species' DNA. Evolutionary process have meant that a retrovirus managed to insert it's own DNA into the mouse DNA (retroviruses replicate by inserting themselves into the host species' own DNA) and it has then entered the DNA of the germ-line cells (sperm and egg cells), and the virus DNA has been passed into the DNA of every cell of the next generation of mice... Over time, the endogenous virus becomes widespread throughout the whole of the species.

So, endogenous retroviruses are encoded in the DNA of the host species.
It is possible to check to see if XMRV or PMRV are lab contaminants from either mouse DNA, or endogenous mouse retroviruses, by checking the genome of XMRV or PMRV against the mouse genome. If the XMRV or PMRV genomes were found to be encoded in mouse DNA, then their discovery might have been due to mouse contaminants, but they aren't in the mouse genome, and there are also many other reasons why XMRV and PMRV have been shown not to be contaminants.

Mouse DNA includes the DNA of endogenous mouse viruses (MLV's) which is why alter checked the genome of his PMRV's against the mouse genome, to see if the PMRV's he detected could be due to contamination from mouse MLV's (endogenous mouse viruses) or mouse DNA. The PMRV's genetic code didn't show up in any of the mouse genomes tested.

The reason that these particular mice cannot be infected with their own endogenous X-type viruses is probably because they have evolved a resistance to infection (see additional notes for clarification). This resistance is achieved by a mutation in the DNA which encodes for the relevant cell wall receptor which the virus would attach to. This means that the MLV cannot attach to the cell wall and gain entry to the cell. However, the endogenous retrovirus DNA, as an integral part of the mouse DNA, can still encode for these viruses, and the mouse cells can create spurious viruses which get pumped into the blood stream. In the resistant strain of mice, the viruses are unable to attach to the mouse cell walls, because of the evolved resistance, and therefore cannot infect, or enter, new cells. It is possible for these viruses to jump species, however, where they can then become fully active and replicating viruses in the new host species. If the mice were to lose their genetic resistance to their own endogenous retroviruses (retroviruses encoded in their own DNA), then the mouse's own DNA would encode and form complete retroviruses which could then infect other cells of the mouse, because there would then be no genetic resistance inhibiting infection by the virus. This would probably be the case in the non-resistant strains.

The 'X' in 'XMRV' refers to a type of MLV virus (Xenotropic MLV) that was already known to science. However, it seems that the 'X' is now a loose term because, since the naming of X-MLV's, more research has been carried out which demonstrates that these viruses behave differently in different strains of mice. Some strains of mice have now been demonstrated as being susceptible to infection by X-type (xenotropic) MLV's because of a genetic difference that alters the relevant receptor of the mouse cell wall. So it seems that 'X' has become purely a name, or categorisation tool, rather than an indicator of function in the wider mouse population. Indeed XMRV also has P-type MLV genetic code in it anyway. 'P' indicates polytropic virus behaviour which means that the virus can infect the cells of the original host species as well as being able to jump to a new species.

We hardly know anything at all about XMRV yet and it's helpful to know as much as we can about it, including whether it is purely a human virus, or a cross-species mouse virus. Knowing for certain that the virus is not present in any mice also helps to prove that XMRV is not a lab contaminant originating from mice.

Some recent research has demonstrated that certain strains of mice are genetically susceptible to infection to XMRV in laboratory conditions, although no XMRV has ever been found in any mice 'in the wild'.

We can't be 100% certain that XMRV is not harboured by any mice because there are so many different varieties and populations of mice in the world, including wild and domestic and lab mice. This means that certain strains of mice are susceptible to different viruses, and diverse mice populations might be exposed to, and harbour, different pathogens.

XMRV has never been found in mice, but it is similar to mouse viruses, so it is possible that XMRV might be hiding in some small mouse population, somewhere. However, at the moment, it looks like XMRV is purely a human virus which probably originated in mice... If this is the case then a mouse virus would have crossed over to the human species at some point in our history, and then the virus would have mutated so that it easily passes from human to human, and easily replicates in humans. When it mutated, it became purely a human virus, as long as it is not passed back to the mouse population. If it is found in the mouse population then it will be a cross-species virus.

One other thing to mention (thanks to anciendaze for pointing this out) is that there could be an intermediate species, between mice and humans, where XMRV originates from. In other words, an MLV could have jumped to another animal species, from mice, where it then mutated into XMRV. And then XMRV could have jumped to humans from the intermediate species.


Additional notes:

This is such a complex subject area.
The earliest study I can find on Xenotropic viruses is authored by Jay Levy, dated 1973: http://www.ncbi.nlm.nih.gov/pubmed/4356281?dopt=Abstract&holding=f1000,f1000m,isrctn
Referring to a Xenotropic virus, the paper says: "it grows only in cells foreign to the host."
This early definition of 'Xenotropic' led me to my earlier error that whole Xenotropic viruses could not grow in mouse cells. Levy's 1973 paper was early research, and the author doesn't seem to be certain that the Xenotropic viruses are endogenous in the strain of mice that he studied, but further research studies show that production and release of Xenotropic endogenous mouse viruses occur spontaneously from the resistant mouse cells.
Earlier in my blog, I have said that the resistant mice owe their resistance to xenotropic viruses due to an evolutionary process. This would mean that sometime in the history of that strain of mouse, a evolutionary selective mutation occurred to the mouse DNA which encoded for the relevant receptor on the mouse's cell walls which made the cells insusceptible to the Xenotropic MLV's. This is said to be the most likely reason for the insusceptibility to infection, but it is also possible that the virus originally infected the mouse using a different receptor.
One of the most simple, authoritative and accurate explanations of the meaning of 'xenotropic' is that xenotropic viruses "do not recognise a receptor on cells of their hosts."
http://books.google.co.uk/books?id=...ruses&pg=PA360#v=onepage&q=xenotropic&f=false (Page 360)

One other thing to add to the discussion is that one paper reports that the 1973 study by Jay Levy discovered that the endogenous xenotropic retrovirus he was studying could infect humans... So why did it taken another 33 years to discover XMRV and PMRV's?

My Sources:
http://www.retrovirology.com/content/3/1/67
http://www.ncbi.nlm.nih.gov/pubmed/4356281?dopt=Abstract&holding=f1000,f1000m,isrctn
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=rv&part=A18
http://books.google.co.uk/books?id=...ruses&pg=PA360#v=onepage&q=xenotropic&f=false
http://books.google.co.uk/books?id=...iruses&pg=PA57#v=onepage&q=xenotropic&f=false
http://jvi.asm.org/cgi/content/abstract/JVI.01863-10v1
http://books.google.co.uk/books?id=...ruses&pg=PA360#v=onepage&q=xenotropic&f=false (Specifically Page 360)
http://jvi.asm.org/cgi/content/abstract/16/4/844
  1. alex3619
    Hi Bob, just a slight correction of a comment you made - DNA is not a protein, it is a string of nucleic acids. DNA is much more fragile than proteins, and RNA is even more fragile than DNA. This means they can both be damaged more easily, and so have a lower half-life in most environments. We have repair enzymes to correct this in human DNA, or we would not live very long. Viruses lack this capacity, so many virus genomes are damaged - the virus does not care as long as enough are intact to infect new hosts. Bye, Alex
  2. meghan
    I hope someone corrects the facts regarding how many retroviruses.
    HTLV-I and HTLV-II both found by Dr. Robert Gallo at Wistar Institute.
    Dr. Gallo also involved in HIV/AIDS...it was originally called HTLV-III

    XMRV and MLV's are the Fourth Retroviruses found in Humans.

    Dr. Elaine DeFrietas co-worker was Dr. Robert Gallo.
    Dr. DeFrietas found the "mapping of HTLV-II like.."
    Testified in Congress April 1990 with the director Dr. H. Kropowski.
    I have the testimony if anyone wants to read it
    Meghan
  3. Dr. Yes
    Hi Bob

    Thanks for clarifying your post!

    In general terms, I think that you are incorrect, Dr Yes, about proteins not being able to jump species, because any contaminant can enter the blood through a cut, for example. For example, Prions are primarily proteins and 'viral particles' are made up of proteins, and DNA is a protein.
    To "jump species" means that a pathogen manages to establish infection in a population of another species. A viral protein by itself cannot jump species because it has no means of replication. It may enter the blood as a contaminant but that would be as a foreign substance alone, not as an actual infectious agent. It is the nucleic acid core of a virus that makes it capable of establishing itself in a new host. Btw, DNA (and RNA) are nucleic acids, not proteins; they are the necessary templates for replication of viruses. Prions are composed of a particular protein with the unique property of setting off a chain reaction of structural change in the same protein within the cells of an infected host... but it's a unique form of 'infection' and 'replication' that doesn't apply to viruses (it's a bit more like the chemical "Ice-nine", if you've ever read "Cat's Cradle"!).

    Whether, in relation to other endogenous retroviruses, partial viral particles can combine with other viral particles to form complete and active retroviruses in a species other than the host species, I don't know... I don't think that I will dig deeper into that area right now.
    Viral envelope proteins from another species can potentially be borrowed by the core of another virus to produce "pseudotyped" hybrids; genetically this remains the same as the original virus and is not a new genetic entity, but the temporary "borrowing" of another virus's envelope may give a virus (such as HIV-1) the ability to infect new cell types that were previously inaccessible to it. This is not the formation of a new retrovirus, however.

    Certain replication incompetent viral genomes from an outside source could in principle recombine with the DNA of existing host viral genomes to produce new replication-competent viruses. This is the principle upon which retroviral vector gene therapy and genetic engineering are based, for example. My brain is too fuzzy to remember any sources that demonstrate this occurring naturally. However, I would assume that these "foreign" viral genomes would have to be almost complete, and be part of a full virion (envelope, matrix, etc. proteins and all) that is capable of infection. Once it infects a host cell, it would be unable to replicate, but it could convert its RNA to DNA and then its DNA could recombine with that of different viruses already in residence in that cell.

    Good luck with any future digging... Sorry I can't suggest more resources right now; I am off on an indefinite leave from posting (or am supposed to be) for health reasons (i.e. I have no "health"!).
  4. Bob
    Thanks very much for that info Dr Yes...
    It seems that I've made a fundamental error with regards to virus behaviour and transmission... I don't know how I managed to get that so wrong... Probably because I'm am amateur, and not a mouse virologist!
    Thanks very much for pointing out my mistakes...
    I've made a few corrections, and I'll work on tidying up the rest later.

    There's a few details I'd like to discuss:

    1. Yes, I used the word 'immunity' incorrectly, and sloppily... The mice would have evolved (probably*) such that their cells were unable to be infected by the endogenous virus, but the word 'immunity' is not accurate. It would have been accurate to say that the mice evolved a 'resistance' or an 'insusceptibility'. I think the difference will be lost on many non-scientists, and so, for clarity, the difference is that 'immunity' relates to an immune system response whereas, in this case, the mouse DNA evolved such that the mice became impervious to infection, based on a change to a receptor on their cell wall, but not based on changes to the immune system. It's similar to the way we don't get infected by many animal viruses... It's not because we have an immune system defense against them all but, rather, the animal viruses do not have an ability to infect us in the first place because they haven't evolved the ability to infect humans.
    *Apparently it's also possible that the mice never had the receptors in the first place, but the virus originally used some other receptor to gain entry to the mouse cells. But most likely the mice adapted by natural selection.

    2. I didn't know that whole xenotropic MLV's could be formed within the original mice that were researched. So thanks for pointing that out, Dr Yes. It looks like I've made a major error here, based on the varied explanations of the word 'Xenotropic' that I found. Do you have a source for the info that describes that viral behaviour, Dr Yes? I had read, many times, that the term 'Xenotropic' indicates that a whole virus cannot be formed, and cannot replicate. But on reading deeper into the research literature, it seems that it actually just means that the host mouse cells cannot be infected due to a mutated cell receptor.

    3. In general terms, I think that you are incorrect, Dr Yes, about proteins not being able to jump species, because any contaminant can enter the blood through a cut, for example. For example, Prions are primarily proteins and 'viral particles' are made up of proteins, and DNA is a protein. But in relation specifically to X-MLV's you are correct that it is the whole virus that jumps species.
    Whether, in relation to other endogenous retroviruses, partial viral particles can combine with other viral particles to form complete and active retroviruses in a species other than the host species, I don't know... I don't think that I will dig deeper into that area right now.

    4. It's interesting that only a certain section of the env gene is used to determine whether the virus should be categorized as Xenotropic or Polytropic. So the 'X' or 'P' applies only to a very small section of the viral DNA/RNA, relating to whether the virus can attach itself to a specific mouse cell wall receptor. The 'X' and 'P' categorisations seem to be almost irrelevant to the virus behaviour, generally speaking, but just correspond to the DNA makeup of a certain small section of viral DNA which determines whether the virus can attach to a specific receptor on the mouse cell wall in a specific strain of mouse. The terms 'Xenotropic' and 'Polytropic' do not reflect the behaviour of the viruses generally, but only describe a small section of viral DNA, and the behaviour of the virus in study/studies on a specific type/types of mouse. Therefore the terms can only be used as a description and cannot be used to describe virus behaviour in the general mouse population. If they had looked at different mouse strains, other than the ones used in the original study/studies which identified these viruses, then they would have named them Polytropic instead of Xenotropic. Basically, they are all mouse Gamma-retroviruses and MLV's.



    Thanks again,
    Bob
  5. Dr. Yes
    Hi Bob!

    Just wanted to correct or clarify a few key points in your post:

    'Xenotropic' indicates that a virus can infect, and replicate in, another species (i.e. in this case, humans) other than the original host species (i.e. mice), but that it cannot infect, or replicate in, the original host species (i.e. mice).
    But in the case of XMRV, 'X' (xenotropic) is referring to behaviour of the mouse viruses (MLV's) that XMRV is similar to... The 'X' is not referring to the behaviour of the new human virus 'XMRV'.
    So, in other words, the X-type MLV's, that XMRV is similar to, can infect other species other than the original mouse host, but they cannot infect, or replicate in, mice.

    The term 'xenotropic' was used to apply to MLVs in certain lab mouse strains (the only ones studied at the time) that were endogenous but could no longer infect cells from those mice. However, some could still be expressed; they just didn't have anywhere to go once they budded from the cells, so the overall quantity of expression was limited. It turns out that these viruses are only 'xenotropic' in those lab mouse strains; in other mouse strains and in most wild mouse species they would qualify as polytropic. What unifies the group known as xenotropic MLVs is that they cannot access cells that have certain variants of the Xpr1 receptor. A small structural change (due to mutation) in those Xpr1 receptors prevents them from being 'hijacked' by this group of viruses, but not by other groups. This means that this group of viruses must share a key envelope structure that does not "match up" properly with the mutated Xpr1 receptor (thus preventing their entry). As one might expect, it turned out that XMLVs are closely related to one another genetically, so grouping them together appears to be phylogenetically appropriate (barring large amounts of recombination). Bear in mind that a virus's host range is determined by only a section of the env gene; thus, a recombinant virus that has just that bit of env borrowed from an XMLV and all the rest from a PMLV would still technically be xenotropic in mice with the restrictive Xpr1 receptors (i.e. even if 99% of it is from a PMLV). This leads to some confusion in terminology, and can potentially make the distinction between X and P much less relevant.

    Lab mice are inbred strains derived from a few different common wild mouse species. Among wild mouse species, the majority have an Xpr1 receptor variant called Xpr1sxv that is perfectly useable by "XMLVs"; these viruses can infect these mouse species readily.

    The evolutionary sequence of events which led to any one xenotropic MLV is believed to have proceeded as follows: first, a polytropic MLV (which also must use the Xpr1 receptor to get into cells) got into the germline of a given mouse population and thus became endogenous in that population. At this stage it could be expressed and infect other mice as well. It might have spread to quite a few other mouse strains. Then at some point, probably during the breeding of mice by humans, a mouse was born with a mutation in its Xpr1 receptor gene. This small mutation resulted in a slightly different receptor structure that did not impair its biological function but just happened to be different enough to disrupt the normal binding process of the endogenous PMLV in question, so that it could no longer enter cells in that mouse. Through natural selection (and probably artificial selection as well), that mutated gene became dominant within a large number of inbred mice; they all had the Xpr1 receptor variant that prevented infection by the virus. Thus, in those mice, that virus's proviral form was locked into the mouse genome and any virions it expressed were locked out of the cell.

    Later, researchers studying these mice noticed this virus's inability to infect cells from the same mice and classified it with other viruses that had the same problem, calling them all "xenotropic".

    The reason that mice can't be infected with their own endogenous X-type viruses is that they have evolved an immunity to the virus. However, the endogenous viruses can still encode for viral particles and proteins, but they can't form whole, replicating viruses in the host mouse species.

    As I explained above, this is not an issue of 'immunity', i.e. the immune system is not involved. Also, endogenous viruses including XMLVs CAN form whole, replicating viruses. Further, the word species is inappropriate, as lab mouse strains do not constitute species.

    It is possible for these viral particles and proteins to jump species, however, where they can then become active viral particles, combine, and form whole, replicating, viruses in the new host species. (i.e. viral particles can jump species where they can then become whole viruses.)

    That's incorrect; viruses can only infect other cells and species if they are 'whole'; viral proteins cannot jump species as they contain no genetic material.

    Some recent research has demonstrated that certain strains of mice are genetically susceptible to infection to XMRV in laboratory conditions, although no XMRV has ever been found in any mice 'in the wild'.

    That's right; the recent research has shown that the majority of mouse species (i.e. wild mice) have a receptor type that allow infection by XMLVs and therefore probably XMRV, and so do a number of common strains of lab mice (whose cells have actually been shown to be vulnerable to XMRV infection). These mice have inherited the earlier form of the Xpr1 gene (Xpr1sxv) that permits XMLV infection, not the later mutated form.
  6. Cort
    I love to hear that about schizophrenia. Did you know that some people with obsessive compulsive disorder develop it, out of the blue, after a bout with an infection???? Its all interesting stuff!
  7. Bob
    Thanks Cort... yes, it's an interesting subject isn't it... Bridgette Huber says that HERV-K18 (the human endogenous retrovirus that she is researching) encodes for a 'superantigen', although I'm not exactly sure what the superantigen is. And I've read that some human endogenous retroviruses also code for essential beneficial parts of our immune system. It's easy to imagine how some endogenous retroviruses could encode for proteins that cause disease... Some scientists are doing research into Schizophrenia to see if it might be caused by endogenous retroviruses.
  8. Cort
    Great job, Bob! :) I thought this was really interesting.

    However, the endogenous viruses can still encode for viral particles and proteins, but they can't form whole, replicating viruses in the host mouse species. It is possible for these viral particles and proteins to jump species, however, where they can then become active viral particles, combine, and form whole, replicating, viruses in the new host species. (i.e. viral particles can jump species where they can then become whole viruses.)

    I guess that applies to humans and endogenous retroviruses as well? They can, at time, encode proteins but not whole viruses. I can see how retrovirologists can get jazzed about their field.