XMRV

Summary of Current Research

XMRV (Xenotropic Murine Leukemia Virus-Related Virus) and other members of the MuLV (Murine Leukemia Virus) family were proposed as new human retroviruses that may be involved in prostate cancer (PC) and chronic fatigue syndrome (CFS) [1, 2]. Non-peer reviewed reports also associated XMRV with Fibromyalgia, Atypical Multiple Sclerosis, Gulf War Syndrome, Autism, Chronic Lyme and other neuro-immune disorders.

A steady stream of publications followed the initial reports finding no association between XMRV and CFS [3, 4, 5, 6, 7, 8, 9, 10, 11, 12], including studies using samples from patients found positive in the original study [13, 14]. Several labs discovered that what they initially thought were positives were actually coming from commercially contaminated tissues or reagents [15, 16, 17]. The genetic signature in XMRV isolates from previous studies was linked to contamination from a commercial cell line [18]. XMRV itself was shown to have been accidentally created in a lab during the 1990’s and could not be responsible for previous CFS outbreaks [19]. Although research suggests that XMRV is capable of infecting cell lines derived from humans in the lab, additional studies have shown that members of the MuLV family, including XMRV, cannot persist in actual human sera [14] or survive replication in human blood cells [20].

Although for some in the CFS community the issue is still under debate, scientists have reached consensus that XMRV is not associated with CFS. The source of contamination in the original study was discovered and the tests used by labs claiming to find XMRV were proven faulty in a separate blinded study [21, 22]. This led to a partial retraction of the original XMRV/CFS paper [21]. An overview from the beginning to the end of the XMRV story can be found in the journal Science, where the original study was published (click here for link).

Cooperative Diagnostics' Involvement

When news hit the press that XMRV was associated with CFS on Oct 8th, 2009, Cooperative Diagnostics used its proprietary bioinformatics and mathematical algorithms to design and launch a commercial test for XMRV/MuLV to accelerate appropriate treatment for those who suffer from CFS. The process from design to finished product, including external validation by an independent CLIA lab, took a record 16 days.

Independent from commercial testing, the company collected samples from CFS and autism patient volunteers. High sensitivity PCR testing confirmed by the United States Center for Disease Control showed that none of the samples were XMRV positive (follow the links for autism study and CFS study publications). Once peer-reviewed publications verified that XMRV was not found in persons with CFS or controls, Cooperative Diagnostics elected to remove its test from the market. While Cooperative Diagnostics is capable of rapid test design for any pathogen or genetic condition, the company's objective is to catalyze personalized treatment of the patient; Cooperative Diagnostics is not in the business of selling tests for viruses that are falsely associated with disease.

If other organizations had possessed Cooperative Diagnostics technological capability, years of research and millions of dollars could have been saved.

Annotated Bibliography

1. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH and Mikovits JA: Detection of an infectious retrovirus, xmrv, in blood cells of patients with chronic fatigue syndrome. Science 2009, 326:585-589

2. Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R and Alter HJ: Detection of mlv-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci U S A 107:15874-15879

3. Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S and Cleare A: Failure to detect the novel retrovirus xmrv in chronic fatigue syndrome. PLoS One 2010, 5:e8519

4. Groom HC, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, Gow JW, Mattes FM, Breuer J, Kerr JR, Stoye JP and Bishop KN: Absence of xenotropic murine leukaemia virus-related virus in uk patients with chronic fatigue syndrome. Retrovirology 2010, 7:10

5. van Kuppeveld FJ, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJ, Swanink CM, Bleijenberg G, Netea MG, Galama JM and van der Meer JW: Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the netherlands: Retrospective analysis of samples from an established cohort. BMJ 2010, 340:c1018

6. Switzer WM, Jia H, Hohn O, Zheng H, Tang S, Shankar A, Bannert N, Simmons G, Hendry RM, Falkenberg VR, Reeves WC and Heneine W: Absence of evidence of xenotropic murine retrovirus-related virus infection in persons with chronic fatigue syndrome and healthy controls from the united states. Retrovirology 2010, 7:57

7. Henrich TX, Li JX, Felsenstein D, Kotton CX, Plenge RX, Pereyra F, Marty FX, Lin NX, Grazioso P, Crochiere DX, Eggers D, Kuritzkes DX and Tsibris AX: Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions. J Infect Dis 2010,

8. Hong P, Li J and Li Y: Failure to detect xenotropic murine leukaemia virus-related virus in chinese patients with chronic fatigue syndrome. Virol J 2010, 7:224

9. Hohn O, Strohschein K, Brandt AU, Seeher S, Klein S, Kurth R, Paul F, Meisel C, Scheibenbogen C and Bannert N: No evidence for xmrv in german cfs and ms patients with fatigue despite the ability of the virus to infect human blood cells in vitro. PLoS One 5:e15632

10. Satterfield BC, Garcia RA, Jia H, Tang S, Zheng H and Switzer WM: Serologic and pcr testing of persons with chronic fatigue syndrome in the united states shows no association with xenotropic or polytropic murine leukemia virus-related viruses. Retrovirology 8:12

11. Erlwein O, Robinson MJ, Kaye S, Wills G, Izui S, Wessely S, Weber J, Cleare A, Collier D and McClure MO: Investigation into the presence of and serological response to xmrv in cfs patients. PLoS One 6:e17592

12. Furuta RA, Miyazawa T, Sugiyama T, Kuratsune H, Ikeda Y, Sato E, Misawa N, Nakatomi Y, Sakuma R, Yasui K, Yamaguti K and Hirayama F: No association of xenotropic murine leukemia virus-related virus with prostate cancer or chronic fatigue syndrome in japan. Retrovirology 8:20

13. Shin CH, Bateman L, Schlaberg R, Bunker AM, Leonard CJ, Hughen RW, Light AR, Light KC and Singh IR: Absence of xmrv and other mlv-related viruses in patients with chronic fatigue syndrome. J Virol

14. Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett J, Qiu X, Luk K-C, Schochetman G, Knox A, Kogelnik AM and Levy JA: No evidence of murine-like gammaretroviruses in cfs patients previously identified as xmrv-infected. Science 2011,

15. Oakes B, Tai AK, Cingoz O, Henefield MH, Levine S, Coffin JM and Huber BT: Contamination of human DNA samples with mouse DNA can lead to false detection of xmrv-like sequences. Retrovirology 7:109

16. Robinson MJ, Erlwein OW, Kaye S, Weber J, Cingoz O, Patel A, Walker MM, Kim WJ, Uiprasertkul M, Coffin JM and McClure MO: Mouse DNA contamination in human tissue tested for xmrv. Retrovirology 7:108

17. Sato E, Furuta RA and Miyazawa T: An endogenous murine leukemia viral genome contaminant in a commercial rt-pcr kit is amplified using standard primers for xmrv. Retrovirology 7:110

18. Hue S, Gray ER, Gall A, Katzourakis A, Tan CP, Houldcroft CJ, McLaren S, Pillay D, Futreal A, Garson JA, Pybus OG, Kellam P and Towers GJ: Disease-associated xmrv sequences are consistent with laboratory contamination. Retrovirology 7:111

19. Paprotka T, Delviks-Frankenberry KA, Cingöz O, Martinez A, Kung H-J, Tepper CG, Hu W-S, Fivash MJ, Coffin JM and Pathak VK: Recombinant origin of the retrovirus xmrv. Science 2011,

20. Chaipan C, Dilley KA, Paprotka T, Delviks-Frankenberry KA, Venkatachari NJ, Hu WS and Pathak VK: Severe restriction of xenotropic murine leukemia virus-related virus replication and spread in cultured human peripheral blood mononuclear cells. J Virol 85:4888-4897

21. Robert H. Silverman, Jaydip Das Gupta, Vincent C. Lombardi, Francis W. Ruscetti, Max A. Pfost, Kathryn S. Hagen, Daniel L. Peterson, Sandra K. Ruscetti, Rachel K. Bagni, Cari Petrow-Sadowski, Bert Gold, Michael Dean, and Judy A. Mikovits: Partial Retraction. Science 2011

22. Graham Simmons, Simone A. Glynn, Anthony L. Komaroff, Judy A. Mikovits, Leslie H. Tobler, John Hackett, Jr., Ning Tang, William M. Switzer, Walid Heneine, Indira K. Hewlett, Jiangqin Zhao, Shyh-Ching Lo, Harvey J. Alter, Jeffrey M. Linnen, Kui Gao, John M. Coffin, Mary F. Kearney, Francis W. Ruscetti, Max A. Pfost, James Bethel, Steven Kleinman, Jerry A. Holmberg, Michael P. Busch, and for the Blood XMRV Scientific Research Working Group (SRWG): Failure to Confirm XMRV/MLVs in the Blood of Patients with Chronic Fatigue Syndrome: A Multi-Laboratory Study. Science 2011