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Wednesday, February 17, 2010

The Case of the Missing Retrovirus

In October 2009, a team led by Vincent C. Lombardi of the Whittemore Peterson Institute reported the presence of a recently discovered virus, XMRV, in 67% of the blood samples from 101 American patients with chronic fatigue syndrome (CFS). XMRV had previously been linked to some cases of prostate cancer.

This sparked intense interest amongst many people and much discussion. But in January this year, Erlwein et al reported that they did not find any evidence of XMRV in the blood of 186 British CFS patients (my post).

Now, a second British study has appeared, and the results are also negative. The paper is Groom et al's Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. They found no XMRV in 170 British CFS patients or 395 healthy controls. VirologyBlog has an excellent summary of the latest paper.

In order to help people interested in this topic, I've put together a quick summary of all the data on XMRV infection in humans. If I've left anything out or made any mistakes, let me know in the comments. I'll try to keep this list up to date with every new publication - because there are sure to be plenty more.

Overall, the most striking thing about these results is the national differences. XMRV has been detected in 67% of American CFS patients, in 10-25% of American prostate cancer cases, and in 3-4% of healthy Americans. By contrast, in Germany, Britain and Ireland, it's only been detected in 2 Germans, out of a grand total of 1,300 or so European people who have been tested so far using a variety of methods. The situation elsewhere is unclear; one study claimed to detect XMRV in 1.5% of healthy Japanese blood donors but this is unpublished, and the methodology is unclear.

Other than that, it's not clear what's going on here, and it seems to me that it would be premature to conclude anything about XMRV and CFS (or, indeed, cancer) at this stage.

*

Last Updated: 06 July 2010
Please let me know if I have omitted any data (published or unpublished)

Published Papers
- CFS

1. Lombardi et al 2009
  • Patients: "CDC Fukuda Criteria and the 2003 Canadian Consensus Criteria... presenting with severe disability... their diagnosis of CFS is based upon prolonged disabling fatigue ... cognitive deficits and reproducible immunological abnormalities ... impaired exercise performance with extremely low VO2 max measured on stress testing."
  • Origin: USA
  • Method A: PCR of DNA from PBMCs
  • Result: 68 of 101 patients (67%), 8 of 218 controls (3.7%)
  • Method B: PBMC reactivity to anti-MLVp30Gag antibodies
  • Result: 19 of 30 patients (63%), 0 of 16 controls (0%)
  • Method C: Plasma immunoreactivity to SFFV-Env
  • Result: 9 out of 18 patients with XMRV, 0 out of 7 controls
2. Erlwein et al 2010
  • Patients: CDC Fukeda criteria "markedly unwell. Few were working, and 19% were members of patient support groups for CFS/ME... The levels of fatigue in this sample were high ... as were levels of disability"
  • Origin: London, UK
  • Method: PCR of DNA from whole blood
  • Result: 0 out of 186 patients (0%)
3. Groom et al 2010
  • Patients: CDC Fukeda criteria
  • Origin: Bristol, Dorset, London, Birmingham, Norfolk and Epsom, UK
  • Method A: PCR of gDNA from PBMCs
  • Result: 0 of 48 patients (0%)
  • Method B: PCR of gDNA, cDNA, or both from PBMCs
  • Result: 0 out of 142 patients (0%), and 157 controls (0%)
  • Method C: Serum immunoreactivity to XMRV
  • Result: 1 out of 160 patients; 25 out of 395 controls; but positives were not considered specific to XMRV, as they also reacted to and neutralized other viruses.
4. Switzer et al 2010 "CDC study"
  • Patients: Recruited by random population telephone screening and symptom quizzing (unlike other studies). CDC Fukeda 1994 criteria (but also referred to in the abstract as the "revised" 1994 CDC criteria) and symptoms not better accounted for by medical illness or "current psychiatric disorders considered exclusionary for CFS, which included current melancholic depression, current or lifetime bipolar disorder or psychosis, substance abuse within 2 years and eating disorders within 5 years".
  • Origin: Wichita, Kansas, USA and Georgia, USA.
  • Method A: Western blotting serology for anti-XMRV antibodies in plasma
  • Result: 0 of 51 patients (0%) and 0 of 53 controls (0%)
  • Method B: ELISA serology for anti-XMRV gag and pol antibodies in plasma, performed by RKI.
  • Result: 0 of 51 patients (0%) and 0 of 53 controls (0%)
  • Method C: PCR of DNA from PBMCs or whole blood for XMRV gag and pol
  • Result: 0 of 50 patients (0%) and 0 of 97 controls (0%)
  • Method D: PCR of DNA for XMRV gag, performed by BSRI.
  • Result: 0 of 50 patients (0%) and 0 of 56 controls (0%)
5. van Kuppeveld et al 2010 "Dutch study"
  • Patients: Oxford Criteria
  • Origin: Netherlands. Recruited and samples taken 1991-1992
  • Method: PCR of cDNA from PBMCs for XMRV integrase and gag
  • Result: 0 of 32 patients (0%), 0 of 43 controls (0%)
Published Papers - Prostate Cancer

6. Urisman et al 2006
  • Patients: Familial Prostate Cancer
  • Origin: Cleveland, USA
  • Method: PCR on prostate cell DNA
  • Result: 9 of 86 (10.4%); associated with R462Q QQ genotype
7. Schlaberg et al 2009
  • Patients: Prostate Cancer
  • Origin: Columbia University Medical Center, USA
  • Method A: PCR on prostate cell DNA
  • Results: 14/223 prostate cancer patients (6.2%), 2/101 non-cancer prostate controls (2.0%). Not associated with R462Q QQ genotype.
  • Method B: XMRV protein expression (cell reactivity to anti-XMRV serum)
  • Results: XMRV protein expression in 54/223 (23%) cases with prostate cancer and in 4/101 (4%) controls. Not associated with R462Q QQ genotype.
8. Hohn et al 2009
  • Patients: Prostate Cancer
  • Origin: Berlin, Germany
  • Method: PCR on prostate cell DNA
  • Result: 0 out of 589 (0%)
  • Method: Serum immunoreactivity to XMRV proteins (gp70 and Gag)
  • Result: 0 out of 146 patients, 0 out of 5 controls (0%)
9. Fischer et al 2008
  • Patients: Non-familial Prostate Cancer
  • Origin: Hamburg, Germany
  • Method: PCR of prostate cell RNA
  • Results: 1/105 patients (0.95%), 1/70 healthy controls (1.42%).
Unpublished Data

10. D'Arcy et al 2008
  • Patients: Prostrate Cancer
  • Origin: Dublin, Ireland
  • Method A: PCR of prostate cell RNA
  • Results: 0 out of 9 (7 R462Q QQ genotype, 2 others) (0%)
  • Notes: Unpublished data presented at a conference.
11. Furata et al 2009
  • Patients: n/a
  • Origin: Japan
  • Method: "antibodies [to XMRV]"
  • Result: 5/300 controls (healthy blood donors) (1.5%)
  • Note: Unpublished data presented at a conference - I can't access the abstract and am relying on Erlwein et al's summary. In the light of Groom et al, we really need to know whether the antibodies were truly specific to XMRV.
12. "The Harvey Alter NIH/FDA Paper"
  • Patients: CFS?
  • Origin: ?
  • Method: ?
  • Result: "We (FDA & NIH) have independently confirmed the Lombardi group findings." according to a conference presentation by Harvey Alter: see here.
  • Notes: Rumored as of 5th July 2010 to be about to appear in PNAS.
13. Qui et al 2010
  • Patients: n/a
  • Origin: U.S. blood donors
  • Method: Blood immunoreactivity to XMRV env, gag, and p15E.
  • Result: "reactivity to all 3 antigens in a low proportion (~0.1%) of US blood donors." n=?
  • Notes: Conference presentation given at the 17th Conference on Retroviruses and Opportunistic Infections 2010.
ResearchBlogging.orgHarriet Groom, et al. (2010). Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome Retrovirology

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