Chronic fatigue syndrome (CFS), also named myalgic encephalitis, is a complex, debilitating illness that likely encompasses more than one entity. CFS is characterized by persistent disabling physical and mental fatigue – lasting for at least six months and without apparent physical cause – that is not improved by bed rest [Prins et al., 2006]. According to the CFS definition from the Centers for Disease Control and Prevention (CDC), in addition to unexplained chronic fatigue, the sufferer may also experience impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, pain in several joints, new headaches, unrefreshing sleep, or malaise after exertion [CDC, 2006]. A viral origin of the disorder has long been suspected as three-quarters of patients have reported having an infection, such as an acute influenza-like illness or infectious mononucleosis, before the onset of CFS [Prins et al., 2006]. Because RNase L dysfunction has also been implicated as a potential cause of CFS [Suhadolnik RJ et al., 1997; Nijs and De Meirleir K, 2005], shortly after the discovery of XMRV among prostate cancer patients, scientists began their search for the same gammaretrovirus in CFS patients [Lombardi et al., 2009].
In the American study by Lombardi and colleagues , investigators detected XMRV genetic sequences in the blood samples of 68 of 101 (68%) CFS patients, compared to only 8 of 218 (3.7%) healthy controls. Using antibody reagents that recognize a broad spectrum of common elements shared among all xenotropic MuLV (of which XMRV is a member), investigators found indirect evidence for the presence of XMRV proteins within the blood cells of CFS patients. Cell culture experiments revealed that patient-derived XMRV was infectious. By directly exposing uninfected permissive cell lines (that are susceptible to infection by XMRV) to infected blood cells or cell-free plasma from CFS patients, it was shown that cell-associated and cell- free transmission of XMRV were possible. This study also provided indirect evidence for the development of an XMRV-specific antibody response in CFS patients, but not in healthy controls [Lombardi et al., 2009].
The study by Lombardi and colleagues  has generated much interest, concern and criticism. For example, the report has been criticized for not providing adequate description of the CFS patients in question, despite the complexity of the disorder [van Kuppeveld et al., 2010]. Some experts also queried whether it is biologically plausible for a single infectious agent to trigger two-thirds of CFS cases [McClure, 2010]. Previously unreported information has recently surfaced in an editorial from the British Medical Journal that the patients in the Lombardi study came from a suspected outbreak of CFS at a village near Lake Tahoe in the mid-1980’s [McClure, 2010]. Hence, even if the XRMV cause of CFS is real, the prevalence of XMRV among these CFS patients might have been overestimated when the finding is extrapolated to the general population. Following the initial publication of the Lombardi study, three independent studies from the UK and the Netherlands found no evidence of XMRV in their CFS patients [Erlwein et al., 2010; Groom et al., 2010; van Kuppeveld et al., 2010], thus injecting further doubt about the validity of the American findings.
At this juncture, there is no conclusive evidence supporting XMRV as the causative agent of CFS. The mechanism by which XMRV triggers CFS continues to be a mystery.