XMRV and ME/CFS – summary and MEA position statement on second UK study published in Retrovirology

This is a more detailed ME Association summary and position statement.  It replaces the one issued shortly after publication of the paper in Retrovirology by Groom et al on 15 February

ABSENCE OF XENOTROPIC MURINE LEUKAEMIA VIRUS-RELATED VIRUS (XMRV) IN UK PATIENTS WITH CHRONIC FATIGUE SYNDROME

RETROVIROLOGY: 2010, 7, 10 (published 15 February 2010)
An abstract of the research paper can be accessed here: http://www.retrovirology.com/content/7/1/10/abstract

The full paper can be accessed via a provisional PDF on the Retrovirology journal site.

Background

A second UK research group has reported that they have been unable to find any laboratory evidence of XMRV (xenotropic murine leukaemia virus-related virus) infection in people with ME/CFS.

This follows another UK study involving Kings College Hospital, London (for patient selection) and Imperial College, London (for laboratory investigation) which, again, found no evidence of XMRV infection in 186 Fukuda defined CFS patients. An MEA statement and link to this KCH/IC paper can be found in the January news archive on the MEA website.

Researchers involved

The latest UK research, which has been published in the on-line edition of Retrovirology, was carried out by a collaborative of very reputable virologists and retrovirologists.  The group includes two researchers – Professor John Gow and Dr Jonathan Kerr – who are already involved in biomedical research into various aspects of ME/CFS and Dr Jonathan Stoye, from the National Institute for Medical Research. Dr Stoye co-authored the editorial in Science that accompanied the paper from the American (WPI et al) group which found evidence of XMRV infection in 68/101 ME/CFS patients and first raised the possibility of a link between XMRV and ME/CFS back in October 2009.  The Science paper, and the accompanying editorial by Coffin and Stoye, can be accessed via the full XMRV summary on the MEA website.

ME/CFS patient selection

The UK research involved the use of stored blood samples taken from two cohorts involving 170 people with Fukuda research defined CFS and three cohorts containing 395 controls (mainly healthy blood donors).

The patient samples came from people with ME/CFS who had been seen in medical clinics in various locations around the UK (ie Birmingham, Bristol, Dorset, Epsom, Glasgow, London, Norfolk), including some supplied by neurologists Professor Peter Behan and Dr Abhijit Chaudhuri.  Unlike the American study, which only involved people with ME/CFS who met both Fukuda CFS research criteria and Canadian clinical criteria for CFS, the UK patients only met Fukuda CFS research criteria.  The reasons why most (possibly all) research groups who are quickly attempting to replicate the US/WPI et al findings are not currently using Canadian clinical criteria are explained in more detail in the MEA summary on XMRV.

Laboratory methods used to detect evidence of XMRV infection

The UK researchers looked for evidence of XMRV infection using two laboratory techniques

Firstly, quantitative PCR (polymerase chain reaction) to check for the presence of viral nucleic acids (ie DNA).  The PCR employed is capable of detecting as few as 16 copies of proviral DNA – viral DNA (genetic material) that has been integrated into human chromosomal DNA.  The authors state that this technique is likely to be as sensitive, if not more so, than the assays used in the US/WPI et al study. No XMRV sequences were detected in 142 CFS samples and in 157 controls.

Secondly, a viral neutralisation assay to try and detect an anti-XMRV immune response. In simple terms this means looking for evidence of antibodies that could prevent infection of cells with the XMRV infection.  None of the 142 CFS samples contained antibodies that could block XMRV infection of the cells.  Although 22/157 control samples were identified that contained neutralising antibody, he authors concluded that the strong positive neutralising activity demonstrated in some of the blood donor controls was not specific to XMRV, and in all likeliness this was not elicited by this virus.  One sample of CFS serum from a separate cohort of 28 was found to contain neutralizing activity

Study conclusions

The authors emphatically report that they have not identified XMRV DNA (ie viral genetic material) in any samples using PCR (0/299).  Some serum samples showed XMRV neutralising activity (26/565) but only one of these positive sera came from a CFS patient.

Those involved in this study concluded that:

No association between XMRV infection and CFS was observed in the samples tested, either by PCR or serological methodologies.  The non-specific neutralisation observed in multiple serum samples suggests that it is unlikely that these responses were elicited by XMRV and highlights the danger of over-estimating XMRV frequency based on serological assays.  In spite of this, we believe that the detection of neutralising activity that did not inhibit VSV-G pseudotyped MLV in at least four human samples indicates that XMRV infection may occur in the general population, although with currently uncertain outcomes.

This is a more detailed ME Association summary and position statement.  It replaces the one issued shortly after publication of the paper in Retrovirology by Groom et al on 15 February

ABSENCE OF XENOTROPIC MURINE LEUKAEMIA VIRUS-RELATED VIRUS (XMRV) IN UK PATIENTS WITH CHRONIC FATIGUE SYNDROM
E

RETROVIROLOGY: 2010, 7, 10 (published 15 February 2010)

An abstract of the research paper can be accessed here: http://www.retrovirology.com/content/7/1/10/abstract

The full paper can be accessed via a provisional PDF on the Retrovirology journal site.

Background

A second UK research group has reported that they have been unable to find any laboratory evidence of XMRV (xenotropic murine leukaemia virus-related virus) infection in people with ME/CFS.

This follows another UK study involving Kings College Hospital, London (for patient selection) and Imperial College, London (for laboratory investigation) which, again, found no evidence of XMRV infection in 186 Fukuda defined CFS patients. An MEA statement and link to this KCH/IC paper can be found in the January news archive on the MEA website.

Researchers involved

The latest UK research, which has been published in the on-line edition of Retrovirology, was carried out by a collaborative of very reputable virologists and retrovirologists.  The group includes two researchers – Professor John Gow and Dr Jonathan Kerr – who are already involved in biomedical research into various aspects of ME/CFS and Dr Jonathan Stoye, from the National Institute for Medical Research. Dr Stoye co-authored the editorial in Science that accompanied the paper from the American (WPI et al) group which found evidence of XMRV infection in 68/101 ME/CFS patients and first raised the possibility of a link between XMRV and ME/CFS back in October 2009.  The Science paper, and the accompanying editorial by Coffin and Stoye, can be accessed via the full XMRV summary on the MEA website.

ME/CFS patient selection

The UK research involved the use of stored blood samples taken from two cohorts involving 170 people with Fukuda research defined CFS and three cohorts containing 395 controls (mainly healthy blood donors).

The patient samples came from people with ME/CFS who had been seen in medical clinics in various locations around the UK (ie Birmingham, Bristol, Dorset, Epsom, Glasgow, London, Norfolk), including some supplied by neurologists Professor Peter Behan and Dr Abhijit Chaudhuri.  Unlike the American study, which only involved people with ME/CFS who met both Fukuda CFS research criteria and Canadian clinical criteria for CFS, the UK patients only met Fukuda CFS research criteria.  The reasons why most (possibly all) research groups who are quickly attempting to replicate the US/WPI et al findings are not currently using Canadian clinical criteria are explained in more detail in the MEA summary on XMRV.

Laboratory methods used to detect evidence of XMRV infection

The UK researchers looked for evidence of XMRV infection using two laboratory techniques

Firstly, quantitative PCR (polymerase chain reaction) to check for the presence of viral nucleic acids (ie DNA).  The PCR employed is capable of detecting as few as 16 copies of proviral DNA – viral DNA (genetic material) that has been integrated into human chromosomal DNA.  The authors state that this technique is likely to be as sensitive, if not more so, than the assays used in the US/WPI et al study. No XMRV sequences were detected in 142 CFS samples and in 157 controls.

Secondly, a viral neutralisation assay to try and detect an anti-XMRV immune response. In simple terms this means looking for evidence of antibodies that could prevent infection of cells with the XMRV infection.  None of the 142 CFS samples contained antibodies that could block XMRV infection of the cells.  Although 22/157 control samples were identified that contained neutralising antibody, he authors concluded that the strong positive neutralising activity demonstrated in some of the blood donor controls was not specific to XMRV, and in all likeliness this was not elicited by this virus.  One sample of CFS serum from a separate cohort of 28 was found to contain neutralizing activity

Study conclusions

The authors emphatically report that they have not identified XMRV DNA (ie viral genetic material) in any samples using PCR (0/299).  Some serum samples showed XMRV neutralising activity (26/565) but only one of these positive sera came from a CFS patient.

Those involved in this study concluded that:

No association between XMRV infection and CFS was observed in the samples tested, either by PCR or serological methodologies.  The non-specific neutralisation observed in multiple serum samples suggests that it is unlikely that these responses were elicited by XMRV and highlights the danger of over-estimating XMRV frequency based on serological assays.  In spite of this, we believe that the detection of neutralising activity that did not inhibit VSV-G pseudotyped MLV in at least four human samples indicates that XMRV infection may occur in the general population, although with currently uncertain outcomes.

Comments from the MEA

These new negative results, along with the negative results from Imperial College, are in stark contrast to the very positive US results reported in Science and they clearly place a large question mark over a possible link between XMRV infection and ME/CFS.  And while the two UK studies have been criticised for not being pure replication studies, because they are not using exactly the same criteria for patient selection, a significant proportion of these UK patients in both studies must have also met the Canadian clinical criteria.  And while differing laboratory protocols were used to test for XMRV,  it is very difficult to find any significant fault with the very thorough laboratory methods used in the new UK study.

Although some scientists will now conclude that the XMRV and ME/CFS debate is over, no firm conclusions can be drawn until we have the results from other studies that are being carried out, or have been completed, that are designed to try and find evidence of XMRV in people with ME/CFS.  Further results from outside the UK should be appearing in the scientific journals in the coming weeks and months. Whilst the two UK studies do not provide any evidence for XMRV infection, they do not completely eliminate a role.

One small but important add on piece of research that The MEA is continuing to pursue is to see if some of those people in the UK who have tested positive for XMRV using the US test can now be retested by one of the UK groups.  It would also be very interesting to see if a mutually agreed cohort of CFS blood samples and control samples can be tested by all three UK and US research groups to see if they produce the same XMRV results.

In the meantime, as the UK researchers point out, it is important to compare samples and protocols between different laboratories in different parts of the world because we do not currently have international agreement on which is the most effective way of testing for evidence of past and present XMRV infection. We also need to find out the exact reason/s why there is such a stark difference between the negative UK results and the positive US results

The ME Association will continue to take a cautious, open-minded and questioning approach to XMRV.  Our advice on XMRV testing remains the same.  We do not believe there is any point, at present, in spending a large sum of money on commercial blood testing for XMRV because the presence of this infection has not yet been shown to be a diagnostic marker for ME/CFS or an aid to management. The accuracy of some of commercial testing also remains uncertain.

The MEA Ramsay Research Fund – https://meassociation.org.uk/index.php?option=com_content&view=article&id=30&Itemid=205 – will continue to consider applications for research funding for any aspect of XMRV research.

XMRV summary

The most recent MEA summary on XMRV can be accessed using the Quick Links section on the MEA website: https://meassociation.org.uk

Dr Charles Shepherd
Hon Medical Adviser, MEA
16 February 2010


ABSENCE OF XENOTROPIC MURINE LEUKAEMIA VIRUS-RELATED VIRUS (XMRV) IN UK PATIENTS WITH CHRONIC FATIGUE SYNDROME
RETROVIROLOGY: 2010, 7, 10 (published 15 February 2010)

An abstract of the research paper can be accessed here.

The full paper can be accessed via a provisional PDF on the Retrovirology journal site.

Background
A second UK research group has reported that they have been unable to find any laboratory evidence of XMRV (xenotropic murine leukaemia virus-related virus) infection in people with ME/CFS.
This follows another UK study involving Kings College Hospital, London (for patient selection) and Imperial College, London (for laboratory investigation) which, again, found no evidence of XMRV infection in 186 Fukuda defined CFS patients. An MEA statement and link to this KCH/IC paper can be found in the January news archive on the MEA website.
Researchers involved
The latest UK research, which has been published in the on-line edition of Retrovirology, was carried out by a collaborative of very reputable virologists and retrovirologists.  The group includes two researchers – Professor John Gow and Dr Jonathan Kerr – who are already involved in biomedical research into various aspects of ME/CFS and Dr Jonathan Stoye, from the National Institute for Medical Research. Dr Stoye co-authored the editorial in Science that accompanied the paper from the American (WPI et al) group which found evidence of XMRV infection in 68/101 ME/CFS patients and first raised the possibility of a link between XMRV and ME/CFS back in October 2009.  The Science paper, and the accompanying editorial by Coffin and Stoye, can be accessed via the full XMRV summary on the MEA website.
ME/CFS patient selection
The UK research involved the use of stored blood samples taken from two cohorts involving 170 people with Fukuda research defined CFS and three cohorts containing 395 controls (mainly healthy blood donors).
The patient samples came from people with ME/CFS who had been seen in medical clinics in various locations around the UK (ie Birmingham, Bristol, Dorset, Epsom, Glasgow, London, Norfolk), including some supplied by neurologists Professor Peter Behan and Dr Abhijit Chaudhuri.  Unlike the American study, which only involved people with ME/CFS who met both Fukuda CFS research criteria and Canadian clinical criteria for CFS, the UK patients only met Fukuda CFS research criteria.  The reasons why most (possibly all) research groups who are quickly attempting to replicate the US/WPI et al findings are not currently using Canadian clinical criteria are explained in more detail in the MEA summary on XMRV.
Laboratory methods used to detect evidence of XMRV infection
The UK researchers looked for evidence of XMRV infection using two laboratory techniques
Firstly, quantitative PCR (polymerase chain reaction) to check for the presence of viral nucleic acids (ie DNA).  The PCR employed is capable of detecting as few as 16 copies of proviral DNA – viral DNA (genetic material) that has been integrated into human chromosomal DNA.  The authors state that this technique is likely to be as sensitive, if not more so, than the assays used in the US/WPI et al study. No XMRV sequences were detected in 142 CFS samples and in 157 controls.
Secondly, a viral neutralisation assay to try and detect an anti-XMRV immune response. In simple terms this means looking for evidence of antibodies that could prevent infection of cells with the XMRV infection.  None of the 142 CFS samples contained antibodies that could block XMRV infection of the cells.  Although 22/157 control samples were identified that contained neutralising antibody, he authors concluded that the strong positive neutralising activity demonstrated in some of the blood donor controls was not specific to XMRV, and in all likeliness this was not elicited by this virus.  One sample of CFS serum from a separate cohort of 28 was found to contain neutralizing activity
Study conclusions
The authors emphatically report that they have not identified XMRV DNA (ie viral genetic material) in any samples using PCR (0/299).  Some serum samples showed XMRV neutralising activity (26/565) but only one of these positive sera came from a CFS patient.
Those involved in this study concluded that:
No association between XMRV infection and CFS was observed in the samples tested, either by PCR or serological methodologies.  The non-specific neutralisation observed in multiple serum samples suggests that it is unlikely that these responses were elicited by XMRV and highlights the danger of over-estimating XMRV frequency based on serological assays.  In spite of this, we believe that the detection of neutralising activity that did not inhibit VSV-G pseudotyped MLV in at least four human samples indicates that XMRV infection may occur in the general population, although with currently uncertain outcomes.
Comments from the MEA
These new negative results, along with the negative results from Imperial College, are in stark contrast to the very positive US results reported in Scienceand they clearly place a large question mark over a possible link between XMRV infection and ME/CFS.  And while the two UK studies have been criticised for not being pure replication studies, because they are not using exactly the same criteria for patient selection, a significant proportion of these UK patients in both studies must have also met the Canadian clinical criteria.  And while differing laboratory protocols were used to test for XMRV,  it is very difficult to find any significant fault with the very thorough laboratory methods used in the new UK study.
Although some scientists will now conclude that the XMRV and ME/CFS debate is over, no firm conclusions can be drawn until we have the results from other studies that are being carried out, or have been completed, that are designed to try and find evidence of XMRV in people with ME/CFS.  Further results from outside the UK should be appearing in the scientific journals in the coming weeks and months. Whilst the two UK studies do not provide any evidence for XMRV infection, they do not completely eliminate a role.
One small but important add on piece of research that The MEA is continuing to pursue is to see if some of those people in the UK who have tested positive for XMRV using the US test can now be retested by one of the UK groups.  It would also be very interesting to see if a mutually agreed cohort of CFS blood samples and control samples can be tested by all three UK and US research groups to see if they produce the same XMRV results.
In the meantime, as the UK researchers point out, it is important to compare samples and protocols between different laboratories in different parts of the world because we do not currently have international agreement on which is the most effective way of testing for evidence of past and present XMRV infection. We also need to find out the exact reason/s why there is such a stark difference between the negative UK results and the positive US results
The ME Association will continue to take a cautious, open-minded and questioning approach to XMRV.  Our advice on XMRV testing remains the same.  We do not believe there is any point, at present, in spending a large sum of money on commercial blood testing for XMRV because the presence of this infection has not yet been shown to be a diagnostic marker for ME/CFS or an aid to management. The accuracy of some of commercial testing also remains uncertain.
The MEA Ramsay Research Fund will continue to consider applications for research funding for any aspect of XMRV research.
XMRV summary
The most recent MEA summary on XMRV can be accessed using the Quick Links section on the MEA website.
Dr Charles Shepherd
Hon Medical Adviser, ME Association
16 February 2010

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