The recent paper by Christine Kozac traces the origins of the XMRV virus and she kills the contamination theory dead. She pretty much follows the MLV virus from around 8 to 12 million years ago or MYA to the present and shows how XMRV arrived in it's present form. The three things that this paper does and it's like the holy grail as far as I'm concerned. Christine Kozak goes on the refrigerator "ABOVE" Dr. Signh and Dr. Mikovits. Now why would I elevator her over Dr. Signh who is so much cuter? (grins)
1-She puts the "contamination question to bed". Period, end of story, any scientist who can read will know this is the end of the line for contamination silliness.
2-She shows that this virus originated around 100 to 130 years ago. Which I blogged about last year and she has confirmed (grins) and my ego is just big enough to really enjoy that. (HUGE GRINS)
3-She's produced a solid primer for researchers about what the potential problems are in regards to this virus. She shows what paths researchers need to follow up on. She shows that this virus has all the markers to produce pathogenesis in lymphocytic leukemia, erythroleukemia, immunodeficiencies, and neurological diseases.
I've laid it out with some quotes and page numbers for anybody that wants to slog through this instead of the 30 or so pages of the paper. Any misinterpretations are mine and mine alone and maybe the result of stupidly, brain fog, or lack of working brain cells. Any mistakes that you find please let me know and I'll correct them.
The paper really does start from the beginning, not as far back as the primordial ooze but close in human terms, (grins) She follows the rise of "XMRV" from 12 Million Years Ago (MYA) to present.
She starts out showing how the receptor (the old XPR1) arose within the species of mice. You have to get to that receptor in order to have XMRV. She knocks out an entire range of mice right out of the gate.
Meaning there are three types of MLV's that have developed in mice. They can be grouped according to the receptors or their ability to bind to cells their RBD's. E-MLV's or ecotropic MLV'S just infect mice and sometimes only the species of mice that they come from. These have an mCAT-1 receptor and are not a problem for humans since we don't have cells that would allow this to bind.
Both PMLV's and XMLV's CAN have the XPR1 receptor that would allow it to bind to human cells and to a range of animal cells but it turns out it's not that easy. There are other factors. First of all many of the virus's are Endogenous so they are bound into the DNA of the mice they are in and don't produce any infectious virus.
However it turns that the nice quite little viruses can, when they come into contacts with other Ecotropic or mouse only virus's, wake up and get busy making a working virus that has the ability to by pass certain restrictive mechanisms and produce a variant [B ]infectious virus. This possibility was discussed in the science community early on regarding XMRV however, it looks like "recombination" is not an issue for the XMRV virus. It looks like it evolved over time to be a straight up novel Exogenous virus.
The XMLV's break out further into groups and are a bit newer on the phylogenetic tree. These virus's break out into three "clades" or subgroupings. Most do not produce infectious virus however within the clades or subgroups there are two that do produce infectious virus the NZB and the F/ST. It is interesting to note however that if certain chemical or bacterial events occur that there are among the non infectious clades or subgroups the ability to produce infectious virus. It doesn't say particularly what these event's might be but the paper treats these as of no importance to the development of XMRV itself.
I'm not sure if it is only in the laboratory or if events of this nature can occur in the wild. (oh, goody more bed time reading) So far all of the virus types that have been discussed can be found in both wild and laboratory mice and have been studied in the laboratory since the 1950's.
I think that's why she sort of stops on page 9 and discusses the problem of contamination. She sites several cell lines that are used to produce a variety of products that have mouse DNA in them and so have virus wrapped up in the DNA. As discussed above some of the quite XMLV can become active if you introduce certain chemicals or bacteria into them. (Note: This is speculation on my part but it appears that many scientist who were not necessarily working with XMRV experiments themselves remembered this bit of information from school days and so jumped on the "could it be contamination" bandwagon, possibly because the ideal of a mouse based endogenous virus being able to infect humans seemed a little 'world is round' to them, grins)
However the above being said she goes on to complete the tracing of the phylogenetic tree of the very unique XMRV and puts the potential of contamination completely to rest. Read on. (if you're not bored, grins)
At this point she looks at the wild mouse and it's origin in the Indian subcontinent 8 to 12 MYA (million years ago) and that the MUS split off from other murinea animals like the hampster and the mink shortly after, around 7 MYA. MUS Then split into 40 subspecies of mice and 3 of those became house mice around 1MYA to 1/2 MYA (I'm gettin' there Mark I swear, grins) from there "fancy mice" or pet mice strains were breed by humans (Note: this goes back to around 1500 C.E. in China and spread to Victorian England where pet mice were very popular, that's just my reading and is not included in the paper) and from "fancy mice" laboratory mice were breed starting in 1905. It turns out that wild mice don't carry the particular type of MLV's that are found in house mice so the phylogenetic tree splits at 1 to 1/2 million years ago and begins to develop in the house mouse strain. Turns out that's why the wild type mouse mus pharia which is being brought into the laboratory in order to study lab virus's is susceptible to the XMRV virus. Note: mus pharia like to play dead and bite. I like these guys already!)
So the MLV's that gave birth to XMRV turn out to be a from house mice rather than wild mice. (no mouse hate for the local field mice please.)
She next notes that Asian mice tend to carry many of the XMLV's while the western European Mus domesticus carries the multiple PMLV's and at the time when M. domesticus was brought to America there does not seem to be an indication of the X/P hybrid that would give rise to XMRV yet. This would indicate that XMRV's developed well after the settling of America or after 1500 to 1600 C.E.
Then it get's interesting. . .
Turns out there is one wild type mouse that produces both Pmv's as well as Xmv's and this is a cross breed found in California (hmmmmm, where was that first out break? Oh yeah in California, grins) This mouse is a cross between M. domesticus with it's multiple PMLV's and Japanese fancy mice which produce XMLV's. These mice where most likely brought over by Chineese and Japanese laborers to the West coast where they hooked up and produced the Lake Casitas, California mouse So we finally have a mouse that has the ability to make an XMRV type virus in the Lake Casitas or LC mouse. However these mice don't produce virus with the correct receptor but with a variation of the receptor called BXV1. Rather than the XPR1 which can get into a lot more cells in a lot more animals.
So far we've gotten our mouse to the west coast of America sometime between 1800 and 1875.
The paper then narrows the field to look at 4 types of things that must be in play for a virus to infect humans and are unique to each MLV.
So you not only have to have and XPR1 host range but a specific type of host range like XPR1n or XPR1(sxv) that seperates where a virus comes from and what it can do. (page 15) Also what "restriction factors" come into play like does your virus get smacked down by APOBEC3G but slide by Trim5 (alpha) then it could only arise from a cross of these viruses. Also a what type of proteins that your virus codes for since they are all different and are there deletions that can pick up junk on the envelope of the virus allowing it to hide. So starting at page 12 Ms. Kozak breaks down how the various mice in the laboratory stack up to produce the XMRV virus.
Two known virus strains have been isolated that produce virus that have shared characteristics of both P and X MLV's however looking at the isolates neither produced XMRV because neither produced the correct receptor to bind with human cells.
The importance of the fact that Christine runs through just about every lab mouse strain over the next few pages and very carefully shows that while a variety of laboratory mice have the ability to produce XMRV which is a cross between XMLV and PMLV none have produced the strain of XMRV that we are seeing in humans. This puts the question of contamination to rest. You could say that this paper is what we have been waiting for. This is the paper we could/can toss into Dr. McClure's face and say "HA". Indeed anybody who want's to shout "contamination" could be effectively extinguished with this paper.
The paper goes on to the next level of XPR1 receptor alleles that are defined by the ability of a particular portion of the receptor ELC's 1 to 4. Turns out you have to have a very specific one in order to infect a range of animals.
In seperating out XMRV from the herd Ms. Kozak shows that while XMRV shares specifics with both known X/P MLV's the overall sequence identity to known viruses that have been studies for years does not reach beyond 94%. When comparing the current copy of XMRV VP62 it has similarities to some X type, some P type and some E types virus's. This shows that it absolutely is not one of the laboratory derived virus's but may have passed through another/other animal(s) before making it's way back to humans. However she qualifies this as saying it's a possibility not a certainty and this is where the rubber pretty much leaves the road.
What makes her think that it is possible that the virus has more than one host is that the receptors XPR1 (sxv), shows up in areas where there are a lot of cases of prostate cancer like the US and Western areas of Europe while the XPR1 (m) group is found in the areas where there is lower incidents of Prostate cancer like Asia, Japan, India and China. She makes a good point but this could be as much about the genetics of the people living in those regions as the receptors on the virus.
She could have a good point in that ME/CFS also shows up more prevalent in Western Europe, America and Australia so there may be some genetic typing much like HTLV which tends to only be pathogenic in the Pacific Rim and Africa.
So that's pretty much it. Nothing that we didn't really know but some really solid science. There is a bit more on potential pathogenic problems on pages 20 to 24 and then some about host restriction factors and recombination possibilities that round it out.
Contamination is DOA
Blog entry posted by George, Dec 2, 2010.