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Possible overview for XMRV viral mechanism

Blog entry posted by George, Jul 15, 2010.

Let me preempt this with a caveat that I'm in over my head on this but since speculation can be fun and there is that desire to push things forward one way or another I just keep poking around in this stuff and the stuff below is what I've come up with. Take it with a grain of salt. (big grins)

First up I don't think we need to be too concerned with any information in the Sandra Ruscetti video file since it's all on her NCI web site. (grins)

The first part of the research mission statement is pretty clear.

Research
The focus of our research is devoted to understanding the molecular basis for the pathogenesis of retrovirus-induced diseases. We have been studying retroviruses that cause leukemia or neurological disease in rodents to obtain basic information on how molecular changes in normal cells can result in pathological consequences. Our current studies are focused on determining whether similar mechanisms may be utilized by the human retrovirus XMRV to cause cancer and neuroimmune diseases in man. Overall, we hope to use the information gained from our studies to design and test rational strategies to counteract the retrovirus-induced molecular events that are responsible for these diseases.

Pasted from <http://ccr.cancer.gov/staff/staff.asp?profileid=5518>

The thing I noticed most during the video and in looking at the wording is that Ruscetti is looking at models for both cancer and neuroimmune although on the neuroimmune front she is using the PVC-211 mouse model which is a neurological degenerative illness. After listening to and looking up more information on the PVC-211 model I sat down and had a really good cry. I'm personally hoping that we don't have anything like that particular model!

Model 1 the SFFV model


The cancer model is pretty straight forward. It goes like more or less like this;

1- They found that the envelope or capsid portion of the XMRV virus has a "deletion" in it much the same as the SFFV MLV that they had been studying. This means that it can stick to another virus or absorb another virus if and only if that virus has Long Term Repeating Sequences that match the deletion portion. This would limit the viruses that it could attract or "recombine" with. It's not like it's going to recombine with polio and give us a new polio virus. It is going to recombine with certain viruses causing the following :
a. Stealth packaging for both (or possible more, head scratch) viruses
b. Envelope protein creation which can cause neuro degeneration but that's a different set of information.

2- This allows XMRV to hook other viruses either in the cell or going into the cell. I'm not well educated enough to discern which viruses it is most likely to hook but I get the impression that the scientist involved have a good ideal and that somehow or another there maybe other MLV's involved as well as a "primary" virus like EBV or HHV-6. But that's about as good as I can make out and that includes information from Dusty Millers (1) recent paper as well.

3- That XMRV the pure form of the virus is present in low copy numbers because most of the virus is transformed into a "recombinate" virus type. Miller's (1) work shows that when XMRV is paired with an Onco(cancer causing) gene from a different virus in this case from Firosarcoma that it will combine and produce more cancer causing cells that are different from the original and therefore escape detection. (This might explain why Elaine DeFrites had problems isolating the virus and why the primer pairs needed to detect the virus didn't always work. If DeFrites was looking at a recombinate viral form then it would change from geographic area to geographic area and would be impossible to actually isolate since it was NOT a pure RNA strand. You could see and discribe a unique viral bud but you would not be able to "isolate" or "clone" the virus. Both have been done with XMRV. So we good)

4- That it is highly infectious because it uses an XPR1 receptor. This doesn't mean infectious between persons but rather infectious within the host's cells. XPR1 is the key to open over 80% of all human cells. So XMRV may not turn out to be the puppet master but rather the key master. Combining with a host of other viruses and providing them the opportunity to enter into cells that they wouldn't normally be able to get into.

5- That XMRV has a very high fidelity rate(2, Kim et al) or that it reproduces each copy of itself exactly. This is unusual in viruses that normally change rapidly in order to stay ahead of the host's immune response. In this case XMRV uses it's perfect copies to attract an attach to other viruses. The attached viruses provide cover for the XMRV and the XMRV provides a key to the cell the other virus needs to get into.

So I think the take home message may be something along these lines. The XMRV is a key to over 80% of the cells in the human body. It reproduces exact copies of itself because it is not a virus that needs to change in order to survive, instead it uses parts of other viruses possibly more than one in order to create a range of quasi species that are able to pass undetected by the host's immune system. Since XMRV has the ability to incorporate more than one type of virus into it's genome it can cause more than one type of cancer and more than one type of disease but it is limited to those viruses that will fit into the deletion sequence that is part of the envelope gene of the XMRV virus.

This would explain why CFS patients have a range of "primary" antibody responses that differ. For instance my antibody response is for EBV which may be what my XMRV is bound to, meaning my body senses that the EBV is their but can't do anything about it no matter how much antibody it throws at it because it is protected by its recombination with XMRV. Someone else may have a "primary" antibody response for HHV-6.

Different recombinations are going to produce slightly different disease patterns, hence the troubling subsets of patients. It also explains why some people get "better" on their own, why others do well on Anti-virals, why Ampligen sometimes works and folks trying Anti-Retrivirals like Dr. Deckhoff-Jones are seeing improvement. Any of these strategies will treat a portion of the problem and give the body a much needed boost to allow it's own anti-viral pathways to engage the XMRV base problem more effectively. However, not everyone responds to any single treatment protocol because it doesn't address the other potential problems present in the patient.

Now if you cook up a cocktail that address' say two or more of the problems then you're cookin on the front burner with gas. But of course as Mindy Kitei (www.cfscentral.com) points out in her excellent summary of the IRIS problem that will have to be addressed as well in order for a treatment program to work.



(1)
J Virol. 2010 Aug;84(15):7908-10. Epub 2010 May 26.
Acutely transforming retrovirus expressing Nras generated from HT-1080 fibrosarcoma cells infected with the human retrovirus XMRV.
Metzger MJ, Miller AD.
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Abstract
Virus from HT-1080 fibrosarcoma cells infected with the human retrovirus XMRV (xenotropic murine leukemia virus-related virus) can induce rare foci of transformation in rat 208F fibroblasts. Characterization of three such foci revealed that one produced an acutely transforming virus at a high titer. The virus consists of a mutant Nras cDNA from the HT-1080 cells inserted into a retroviral vector (added to the HT-1080 cells as a marker for infection) in place of internal vector sequences. These results show that XMRV can generate acutely transforming viruses at a low rate, as is typical of other replication-competent retroviruses, and reveal the potential for transforming virus contamination of retroviral vectors made from transformed cell lines.
PMID: 20504941 [PubMed - in process]PMCID: PMC2897646 [Available on 2011/2/1]

Pasted from <http://www.ncbi.nlm.nih.gov/pubmed/20504941>

(2)PLoS One. 2010 Apr 20;5(4):e10255.
Fidelity of target site duplication and sequence preference during integration of xenotropic murine leukemia virus-related virus.
Kim S, Rusmevichientong A, Dong B, Remenyi R, Silverman RH, Chow SA.
Biomedical Engineering Interdepartmental Program, University of California Los Angeles, Los Angeles, California, United States of America.
Abstract
Xenotropic murine leukemia virus (MLV)-related virus (XMRV) is a new human retrovirus associated with prostate cancer and chronic fatigue syndrome. The causal relationship of XMRV infection to human disease and the mechanism of pathogenicity have not been established. During retrovirus replication, integration of the cDNA copy of the viral RNA genome into the host cell chromosome is an essential step and involves coordinated joining of the two ends of the linear viral DNA into staggered sites on target DNA. Correct integration produces proviruses that are flanked by a short direct repeat, which varies from 4 to 6 bp among the retroviruses but is invariant for each particular retrovirus. Uncoordinated joining of the two viral DNA ends into target DNA can cause insertions, deletions, or other genomic alterations at the integration site. To determine the fidelity of XMRV integration, cells infected with XMRV were clonally expanded and DNA sequences at the viral-host DNA junctions were determined and analyzed. We found that a majority of the provirus ends were correctly processed and flanked by a 4-bp direct repeat of host DNA. A weak consensus sequence was also detected at the XMRV integration sites. We conclude that integration of XMRV DNA involves a coordinated joining of two viral DNA ends that are spaced 4 bp apart on the target DNA and proceeds with high fidelity.

Pasted from <http://www.ncbi.nlm.nih.gov/pubmed/20421928>
  1. dschlindwein
    Yes, thank you for the excellent post. I appreciate your ability to write about this research at exactly the level that an educated non-biologist like me can understand.
  2. capemark
    George,

    This is fascinating. I've never heard of viruses combining with other viruses as a defense strategy before! Kind of scary. Wow, this is complex! (I guess its just our little contribution to science.)

    Thanks for this informative entry.

    Mark Elliott