Xenotropic Murine Leukemia Virus-Related Virus (XMRV) and the Safety of the Blood Supply

Abstract

In 2006, a new virus, xenotropic murine leukemia virus-related virus (XMRV), was discovered in a cohort of U.S. men with prostate cancer. Soon after this initial finding, XMRV was also detected in samples from patients with chronic fatigue syndrome (CFS). The blood community, which is highly sensitive to the threat of emerging infectious diseases since the HIV/AIDS crisis, recommended indefinite deferral of all blood donors with a history of CFS. As XMRV research progressed, conflicting results emerged regarding the importance of this virus in the pathophysiology of prostate cancer and/or CFS. Molecular biologists traced the development of XMRV to a recombination event in a laboratory mouse that likely occurred circa 1993. The virus was propagated via cell lines derived from a tumor present in this mouse and spread through contamination of laboratory samples. Well-controlled experiments showed that detection of XMRV was due to contaminated samples and was not a marker of or a causal factor in prostate cancer or CFS. This paper traces the development of XMRV in the prostate and CFS scientific communities and explores the effect it had on the blood community.

FIG 1

Characterization of CWR22 xenografts and XMRV-related sequences. The genesis of the 22Rv1 and CWR-R1 cell lines is shown. Bold letters indicate samples from which genomic DNA (gDNA) or nucleic acid was available for analysis. XMRV-positive samples are boxed. (Reproduced from reference with the permission of the American Association for the Advancement of Science, with additional information from reference .)

FIG 2

Predicted recombinant formed by pre-XMRV-1 and pre-XMRV-2 is nearly identical to XMRV. Alignment of plots of pre-XMRV-1 and pre-XMRV-2 reveals the reciprocal and largely nonoverlapping regions of near identity to XMRV. The predicted recombinant and the four nucleotide differences from the consensus XMRV sequence are shown, including the six template-switching events. (Reproduced from reference with the permission of the American Association for the Advancement of Science.)

FIG 3

Sensitivity testing for XMRV in laboratories. Analytic sensitivity of spiked XMRV detection in multiple labs is shown. An investigation of XMRV involved carefully controlled testing of sensitivity for different XMRV assays. Serial dilutions of XMRV-infected cells were assayed in triplicate. Labs used a variety of techniques for detection, including nested PCR, quantitative PCR, and transcription-mediated amplification. Abbreviations: GP, GenProbe; FDA(H), lab of Hewlett; FDA(Lo), lab of S. C. Lo; WPI, Whittemore Peterson Institute; NCI, National Cancer Institute. Colors: red, 3/3 positive; orange, 2/3 positive; yellow, 1/3 positive; white, 0/3 positive. Replicates of six negative samples were performed, and white represents 0/6 while green represents 1/6 replicates being positive. In the cases of FDA(Lo) and WPI, subsequent sequencing demonstrated in each case that the amplification product in the single false-positive result for a negative-control sample was of human genomic origin. In the case of GP, a repeat by a separate operator yielded 0/6 controls as positive. (Reproduced from reference with permission of John Wiley and Sons.)

FIG 4

Results of blind panel testing. Blood was collected from four patients with CFS found to be XMRV positive in the 2009 Whittemore Peterson Institute (WPI) study published in Science, as well as XMRV/MRV-negative controls. Specimen tubes were then divided into three groups, with one set immediately processed into peripheral blood mononuclear cells (PBMC), whole blood, and plasma, while the other two sets were refrigerated and then similarly processed after 2 and 4 days. These samples were coded, blinded, and distributed to three laboratories—the CDC, the National Cancer Institute (NCI), and the WPI, as well as to GenProbe. False-positive results were reported by the Whittemore Peterson Institute (Lombardi) laboratory. DRP, HIV Dynamics and Replication Program. (Based on data from reference .)