XMRV – American ME and CFS Society

False Alarm: XMRV, Cancer, and Chronic Fatigue Syndrome

Abstract:

Xenotropic murine leukemia virus (MLV)-related virus (XMRV) was first described in 2006 in some human prostate cancers. But it drew little attention until 2009, when it was also found, as infectious virus and as MLV-related DNA, in samples from people suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This discovery was rapidly followed by efforts of the international research community to understand the significance of the association and its potential to spread widely as an important human pathogen.

Within a few years, efforts by researchers worldwide failed to repeat these findings, and mounting evidence for laboratory contamination with mouse-derived virus and viral DNA sequences became accepted as the explanation for the initial findings. As researchers engaged in these studies, we present here a historical review of the rise and fall of XMRV as a human pathogen, and we discuss the lessons learned from these events.

Source: Coffin JM, Kearney MF. False Alarm: XMRV, Cancer, and Chronic Fatigue Syndrome. Annu Rev Virol. 2024 Jul 8. doi: 10.1146/annurev-virology-111821-125122. Epub ahead of print. PMID: 38976866. https://pubmed.ncbi.nlm.nih.gov/38976866/

XMRV and Public Health: The Retroviral Genome Is Not a Suitable Template for Diagnostic PCR, and Its Association with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Appears Unreliable

Abstract:

A few years ago, a highly significant association between the xenotropic murine leukemia virus-related virus (XMRV) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex debilitating disease of poorly understood etiology and no definite treatment, was reported in Science, raising concern for public welfare. Successively, the failure to reproduce these findings, and the suspect that the diagnostic PCR was vitiated by laboratory contaminations, led to the retraction of the paper.

Notwithstanding, XMRV continued to be the subject of researches and public debates. Occasional positivity in humans was also detected recently, even if the data always appeared elusive and non-reproducible. In this study, we discuss the current status of this controversial association and propose that a major role in the unreliability of the results was played by the XMRV genomic composition in itself. In this regard, we present bioinformatic analyses that show: (i) aspecific, spurious annealings of the available primers in multiple homologous sites of the human genome; (ii) strict homologies between whole XMRV genome and interspersed repetitive elements widespread in mammalian genomes. 'To further detail this scenario, we screen several human and mammalian samples by using both published and newly designed primers.

The experimental data confirm that available primers are far from being selective and specific. In conclusion, the occurrence of highly conserved, repeated DNA sequences in the XMRV genome deeply undermines the reliability of diagnostic PCRs by leading to artifactual and spurious amplifications. Together with all the other evidences, this makes the association between the XMRV retrovirus and CFS totally unreliable.

Source: Panelli S, Lorusso L, Balestrieri A, Lupo G, Capelli E. XMRV and Public Health: The Retroviral Genome Is Not a Suitable Template for Diagnostic PCR, and Its Association with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Appears Unreliable. Front Public Health. 2017 May 22;5:108. doi: 10.3389/fpubh.2017.00108. ECollection 2017. http://journal.frontiersin.org/article/10.3389/fpubh.2017.00108/full (Full article)

A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus

Abstract:

The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. I

MPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen discovery that may be helpful to others working in this field.

Source: Alter HJ, Mikovits JA, Switzer WM, Ruscetti FW, Lo SC, Klimas N, Komaroff AL, Montoya JG, Bateman L, Levine S, Peterson D, Levin B, Hanson MR, Genfi A, Bhat M, Zheng H, Wang R, Li B, Hung GC, Lee LL, Sameroff S, Heneine W, Coffin J, Hornig M, Lipkin WI. A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus. MBio. 2012 Sep 18;3(5). pii: e00266-12. doi: 10.1128/mBio.00266-12. Print 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448165/ (Full article)

Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors

MEDICAL SCIENCES Retraction for “Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors,” by Shyh-Ching Lo, Natalia Pripuzova, Bingjie Li, Anthony L. Komaroff, Guo-Chiuan Hung, Richard Wang, and Harvey J. Alter, which appeared in issue 36, September 7, 2010, of Proc Natl Acad Sci USA (107:15874–15879; first published August 23, 2010; 10.1073/pnas.1006901107).

Retraction of: 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. 2010]

Source: Lo SC, Pripuzova N, Li B, Komaroff AL, Hung GC, Wang R, Alter HJ. Retraction for Lo et al., 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. 2012 Jan 3;109(1):346. doi: 10.1073/pnas.1119641109. Epub 2011 Dec 27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252929/ (Full article)

Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study

Abstract:

Murine leukemia viruses (MLVs), including xenotropic-MLV-related virus (XMRV), have been controversially linked to chronic fatigue syndrome (CFS). To explore this issue in greater depth, we compiled coded replicate samples of blood from 15 subjects previously reported to be XMRV/MLV-positive (14 with CFS) and from 15 healthy donors previously determined to be negative for the viruses. These samples were distributed in a blinded fashion to nine laboratories, which performed assays designed to detect XMRV/MLV nucleic acid, virus replication, and antibody. Only two laboratories reported evidence of XMRV/MLVs; however, replicate sample results showed disagreement, and reactivity was similar among CFS subjects and negative controls. These results indicate that current assays do not reproducibly detect XMRV/MLV in blood samples and that blood donor screening is not warranted.

Source: Simmons G, Glynn SA, Komaroff AL, Mikovits JA, Tobler LH, Hackett J Jr, Tang N, Switzer WM, Heneine W, Hewlett IK, Zhao J, Lo SC, Alter HJ, Linnen JM, Gao K, Coffin JM, Kearney MF, Ruscetti FW, Pfost MA, Bethel J, Kleinman S, Holmberg JA, Busch MP; 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 Nov 11;334(6057):814-7. doi: 10.1126/science.1213841. Epub 2011 Sep 22. Collaborators (25) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299483/ (Full article)

No detectable XMRV in subjects with chronic fatigue syndrome from Quebec

Abstract:

We investigated the presence of XMRV in a cohort of Quebec patients with chronic fatigue syndrome (CFS). DNA was purified from activated peripheral blood mononuclear cells (PBMCs) and PCR was used to detect XMRV gag and env in 72 patients. Anti-XMRV antibodies were searched in sera of 62 patients by Western blot analysis. Attempts to detect XMRV antigens was made, using immunofluorescence with Gag anti-p30 antiserum on activated PBMC from 50 patients. Plasma viremia was measured by RT-PCR on 9 subjects. Finally, detection of infectious virus in 113 CFS subjects was made by co-culture of PHA+IL-2 activated PBMC with human LNCaP carcinoma cells, and by infecting the same susceptible cells with plasma, using a reverse transcriptase (RT) assay as a readout in both experiments. No detection of XMRV footprints nor infectious virus was detected with any of the approaches, in any of the tested individuals.

Source: Cool M, Bouchard N, Massé G, Laganière B, Dumont A, Hanna Z, Phaneuf D, Morisset R, Jolicoeur P. No detectable XMRV in subjects with chronic fatigue syndrome from Quebec. Virology. 2011 Nov 10;420(1):66-72. doi: 10.1016/j.virol.2011.08.018. Epub 2011 Sep 16. https://www.ncbi.nlm.nih.gov/pubmed/21925693

Xenotropic murine leukemia virus-related virus in monozygotic twins discordant for chronic fatigue syndrome

Abstract:

A recent report suggested an association between xenotropic murine leukemia virus-related virus (XMRV) and chronic fatigue syndrome (CFS). If confirmed, this would suggest that antiretroviral therapy might benefit patients suffering from CFS. We validated a set of assays for XMRV and evaluated the prevalence of XMRV in a cohort of monozygotic twins discordant for CFS. Stored peripheral blood mononuclear cell (PBMC) samples were tested with 3 separate polymerase chain reaction (PCR) assays (one of which was nested) for XMRV DNA, and serum/plasma was tested for XMRV RNA by reverse transcription (RT)-PCR. None of the PBMC samples from the twins with CFS or their unaffected co-twins was positive for XMRV, by any of the assays. One plasma sample, from an unaffected co-twin, was reproducibly positive by RT-PCR. However, serum from the same day was negative, as was a follow-up plasma sample obtained 2 days after the positive specimen. These data do not support an association of XMRV with CFS.

Source: Jerome KR, Diem K, Huang ML, Selke S, Corey L, Buchwald D.Xenotropic murine leukemia virus-related virus in monozygotic twins discordant for chronic fatigue syndrome. Diagn Microbiol Infect Dis. 2011 Sep;71(1):66-71. doi: 10.1016/j.diagmicrobio.2011.06.003. Epub 2011 Jul 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158821/ (Full article)

No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected

Abstract:

Members of the gammaretroviruses–such as murine leukemia viruses (MLVs), most notably XMRV [xenotropic murine leukemia virus (X-MLV)-related virus–have been reported to be present in the blood of patients with chronic fatigue syndrome (CFS).

We evaluated blood samples from 61 patients with CFS from a single clinical practice, 43 of whom had previously been identified as XMRV-positive. Our analysis included polymerase chain reaction and reverse transcription polymerase chain reaction procedures for detection of viral nucleic acids and assays for detection of infectious virus and virus-specific antibodies.

We found no evidence of XMRV or other MLVs in these blood samples. In addition, we found that these gammaretroviruses were strongly (X-MLV) or partially (XMRV) susceptible to inactivation by sera from CFS patients and healthy controls, which suggested that establishment of a successful MLV infection in humans would be unlikely. Consistent with previous reports, we detected MLV sequences in commercial laboratory reagents. Our results indicate that previous evidence linking XMRV and MLVs to CFS is likely attributable to laboratory contamination.

Comment in: Prostate cancer: XMRV–contaminant, not cause? [Nat Rev Urol. 2011]

Source: Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett J Jr, Qiu X, Luk KC, Schochetman G, Knox A, Kogelnik AM, Levy JA. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science. 2011 Jul 1;333(6038):94-7. doi: 10.1126/science.1204963. Epub 2011 May 31. https://www.ncbi.nlm.nih.gov/pubmed/21628393

Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature

Abstract:

BACKGROUND: The recent identification of xenotropic murine leukemia virus-related virus (XMRV) in the blood of patients with chronic fatigue syndrome (CFS) establishes that a retrovirus may play a role in the pathology in this disease. Knowledge of the immune response might lead to a better understanding of the role XMRV plays in this syndrome. Our objective was to investigate the cytokine and chemokine response in XMRV-associated CFS.

MATERIALS AND METHODS: Using Luminex multi-analyte profiling technology, we measured cytokine and chemokine values in the plasma of XMRV-infected CFS patients and compared these data to those of healthy controls. Analysis was performed using the Gene Expression Pattern Analysis Suite and the Random Forest tree classification algorithm.

RESULTS: This study identifies a signature of 10 cytokines and chemokines which correctly identifies XMRV/CFS patients with 93% specificity and 96% sensitivity.

CONCLUSION: These data show, for the first time, an immunological pattern associated with XMRV/CFS.

Source: Lombardi VC, Hagen KS, Hunter KW, Diamond JW, Smith-Gagen J, Yang W, Mikovits JA. Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature. In Vivo. 2011 May-Jun;25(3):307-14. https://www.ncbi.nlm.nih.gov/pubmed/21576403

XMRV, prostate cancer and chronic fatigue syndrome

Abstract:

BACKGROUND: A new retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), was identified in 2006 and an association was claimed between it and a genetic polymorphism predisposing to cancer of the prostate. In 2009 the same virus was identified in a cohort of patients with chronic fatigue syndrome (CFS). In 2010 a second related virus was identified in a separate group of CFS patients. A series of studies from disparate geographical areas have failed to substantiate this work. Most recently several papers have suggested that the detection of these viruses was explained by laboratory contamination.

SOURCES OF DATA: All papers including the wording XMRV were abstracted from the NIH library of medicine database and included in the analysis.

AREAS OF AGREEMENT: XMRV is a newly described retrovirus whose nucleic acid has been identified in samples from patients with both prostate cancer and CFS.

AREAS OF CONTROVERSY: Opinions differ as to whether the detected nucleic acid indicates infection with this virus in this disease or whether laboratory contamination of samples accounts for its presence.

GROWING POINTS: An increasing number of papers now refute the association of XMRV with human disease in humans although there is some evidence of serological reactivity to the virus. While it is unlikely that XMRV is a major cause of either prostate cancer or CFS, it can infect human cells and might yet have a role in human disease.

AREAS TIMELY FOR DEVELOPING RESEARCH: Further studies to either prove or disprove the disease association of the virus are ongoing.

Source: Kenyon JC, Lever AM. XMRV, prostate cancer and chronic fatigue syndrome. Br Med Bull. 2011;98:61-74. doi: 10.1093/bmb/ldr010. Epub 2011 May 6. https://www.ncbi.nlm.nih.gov/pubmed/21551158