Does the NO/ONOO- cycle theory dovetail with XMRV?  Yes it does, although not perhaps the way you are thinking.   XMRV is a retrovirus whose replication is stimulated by a transcription factor called NF-kappa B, a transcription factor whose activity is elevated by the NO/ONOO- cycle mechanism.  Consequently the NO/ONOO- cycle will be expected to stimulate XMRV replication.  Retroviral replication is also often found to be stimulated by depletion of reduced glutathione and reduced glutathione depletion is always produced by oxidative stress, another element of the NO/ONOO- cycle.  There are also changes in the immune system that are produced by the cycle, so these may stimulate XMRV replication, as well.  All of these considerations suggest that XMRV may be an opportunistic infection in CFS/ME, one that may contribute to the disease but is not the central cause of CFS/ME.  There are other observations made by Mikovits and her colleagues that suggest an opportunisitic infection.  They report that XMRV occurs in some other diseases, so it is not specific to CFS/ME and they also report that it has a very low copy number in CFS/ME and both of those observations are more easily explained if its role is opportunistic.  I want to emphasize that this does not argue that the XMRV finding is unimportant but it does argue that it is not the central cause of CFS/ME.

Whenever one wishes to make a case that a specific mechanism is the central cause of a disease, it is necessary to look at a number of types of evidence that will each provide evidence for such causality.  In the case of the NO/ONOO- cycle, I have described five principles underlying the cycle, and in most cases, one needs to have sustantial evidence for all five to make a substantial case for the causality of the cycle.   We have such substantial evidence for each of the five principles being fulfilled in CFS/ME, arguing that it is the central cause of this disease. 

To make a case for an infectious agent having such a central role, one needs to make a case for what are known as Koch’s postulates, or perhaps an updated, more modern version of Koch’s postulates.  Mikovits and her colleagues do not claim to have shown that any modern version of Koch’s postulates have been fulfilled for XMRV and CFS/ME.  Consequently, they have not claimed any central causality of this virus. 

Some of the observations for fulfillment of the principles for the NO/ONOO- cycle argue against any central causality of XMRV.  For example there is published evidence that about two dozen agents that are predicted to lower various aspects of the NO/ONOO- cycle, are useful in therapy in CFS/ME, in fibromyalgia or in both.  It is difficult to see how one can argue for centrality of XMRV when such clinical evidence argues for a different mechanism – for a NO/ONOO- cycle mechanism.

Let me make one other additional comment.  I know that some of you have been interested in XMRV because it argues against all of the psychological claims that have been made.  And yes it does do so.  But so do a whole series of published studies, showing genuine and often reproducible studies, documenting major changes in the biochemistry and physiology of many CFS/ME patients.  For example increases in oxidative stress have been shown in at least 20 different studies, mitochondrial dysfunction have been shown in about half the number of studies, as has been increases in inflammatory markers.  There are also changes in blood circulation including orthostatic intolerance and often cardiac dysfunction and a variety of other changes.  There are changes in immune function including low NK cell activity.  All of these changes clearly show that CFS/ME is NOT predominantly a psychological disease.  Anyone who makes these kind of psychological claims should be challenged as someone who is ignoring most of the scientific literature on CFS/ME.  You cannot claim to be doing science while ignoring most of the scientific literature.  In dealing with the issue of the psychological claims, it is a mistake, in my view, to focus on XMRV while ignoring many other studies that have been already repeated in the literature.

The NO/ONOO- cycle mechanism explains each of these changes.  It also explains, and indeed predicts the huge variation that one sees from one patient to another in these and in other properties, thus explaining another of the great puzzles about CFS/ME and also related diseases.  And the improvements seen on treatment with agents that lower parts of the NO/ONOO- cycle point the way to THE most promising approach to therapy, in my judgment.