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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.
Highlights
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating disease of poorly understood etiology
Non-reproducible bands, often associated with extra-bands, characterized a negligible sample of human patients, the second laboratory mouse strain (Ts65Dn, for which we can hypothesize a contribution of PreXMRV2 from one of the progenitor strains) and wood mice
Our bioinformatic searches and screening of human and animal samples pointed out the pivotal role played, in the diagnostic PCR, by the strong homology between the xenotropic murine leukemia virus-related virus (XMRV) genome and repetitive sequences, often of retroviral origin, of house mouse’s genome
Summary
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, debilitating disease of poorly understood etiology. We would like to suggest that at the origin of these misinterpretations and elusive PCR data, which generated frustration in many patients with regard to the possible availability of therapies for diseases with no treatment, there could have been other co-causes that played major roles, in particular: (i) Aspecific, spurious annealings of the primers described by Lombardi et al in a number of sites of the human genome.
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