Thanks rrr for doing this!!! Ask Coffin if he has seen the research article on XMRV's preferred places for inserting itself into cellular DNA:
The article title is: Fidelity of target site duplication and sequence preference during integration of xenotropic murine leukemia virus-related virus (see abstract below).
This article would seem to provide evidence for a causal link between CFS and XMRV because the retrovirus' preferred places for inserting into the cell's DNA are in the CREB and NFAT genes. These are genes that perform functions that are disturbed in CFS patients.
Below are some notes I took on Gerwyn's analysis of this research article.
[Gerwyn, help me out!!]
Gerwyn on XMRV DNA Target Sites
NFAT genes regulate our automatic body processes that are controlled by the autonomic nervous system. If these becomes dysfunctional then we are left with the neuroendocrine symptoms of ME/CFS --
Sensitivity to lights
Sensitivity to sound
High resting heartrate
Postural Orthostatic Tachychardia Syndrome (POTS)
Poor temperature control and so on.
The organic thermostat that controls all these functions is the hypothalamus in the brain. When any function such as heart rate strays outside the normal range, this is detected by the hypothalamus and brought back into normal ranges by the action of the pituitary gland and the Adrenal cortex (and medulla).
If this control system breaks down, our autonomic functions go haywire.
The "molecular thermostat" of the immune system is the NFAT genes (amoung others). The retrovirus XMRV inserts itself into the part of our DNA that contains these genes, the retrovirus XMRV can act as a "molecular dimmer switch" for this gene and affect the levels of its activity and in turn the levels of various chemical components of the immune system.
One example would be that if one of the NFAT genes was upregulated by the "dimmer switch" being turned up, then the level of circulating cytokines would be high. There would be chronic levels of inflammation in multiple body systems.
This would lead to a number of consequences:
Raised levels of abdominal fat
Impaired Glucose tolerance and increased insulin resistance
Alzheimers type symptoms
Cardiovascular abnormalities
Increased risk of stroke
Postural Orthostatic Tachychardia or Hypotension
Impaired blood flow to the brain.
These increased cytokine levels (interferon and interleukins) can lead to Metabolic Syndrome.
Raised interferon levels lead to hyper stimulation of the Tumor Necrosis Factor (TNF) alpha gene. This can lead to high levels of Nitric oxide which in turn depletes glutathione directly and indirectly, damaging mitochondria and creating a partial block in the methylation cycle.
Raised TNF alpha leads to muscle fatigue and pain.
This also reduces BDFN gene expression (also caused by blocking CREB genes) reducing fat oxidation and further compounding problems with fatigue, cognitive problems like memory, dyscalculia, dyslexia and so on
CREB and NFAT co regulate each other just to make life really interesting!!!!
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Fidelity of target site duplication and sequence preference during integration of xenotropic murine leukemia virus-related virus
Abstract
PLoS One. 2010 Apr 20;5(4):e10255.
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.
