Feeling tired? Blame it on a virus.

Chronic fatigue syndrome (CFS), as the name suggests, leads to extreme tiredness in people over many years, and unlike the fatigue most of us feel after hard work or an acute illness, is not relieved by rest. Think of it like you feel during a cold, except that it lasts years.

There are estimates that CFS may affect about 1% of the world population. Though viral etiologies have been suggested, including the involvement of enteroviruses and herpesviruses, the cause of CFS has remained unknown. A new report in the magazine Science, shows the association of a retrovirus, called XMRV (xenotropic murine leukemia virus-related virus), to CFS. This virus was earlier implicated in prostate cancer, one of the most common cancers in men.

Is there anything common between prostrate cancer and CFS? Its too early to say, but lets look at the science and the evidence.

A report in 2006 in the journal PLoS Pathogens first showed the presence of XMRV in prostate cancer patients. Hereditary prostate cancer (HPC), which accounts for 43% of early onset cases and about 9% of all cases, is due to germline mutations in HPC genes. Robert Silverman and colleagues at the Cleveland Clinic Foundation found the HPC1 gene to code for RNase L, a protein involved in antiviral immunity. This suggested the possibility that chronic viral infections might predispose men to prostate cancer.  Together with Joseph DeRisi and Don Ganem at the University of California San Francisco, Silverman discovered XMRV in tumor-bearing prostate tissues (picture below). Interestingly, XMRV was present in prostate tissues of men who have a variant HPC1 gene (which makes a reduced activity variant of RNase L), but rarely in men with the wild type gene making normal RNase L.

The recent Science paper by Judy Mikovits' group from the Whittemore Pederson Institute in Reno (Nevada, USA) and collaborators at the National Cancer Institute in Frederick (Maryland, USA) shows that 67% of CFS patients, but only 3.7% of healthy persons, had XMRV in their blood. In cell culture experiments, these workers also demonstrated that XMRV obtained from CFS patients is infectious and can be transmitted from an infected cell to a healthy cell.

Is XMRV the cause of CFS? This is not proven yet. We only have an association. XMRV was detected in the blood of 68 of 101 CFS patients. What about the other 33? They may have levels of XMRV too low to detect by molecular methods (though I doubt this very much), or there may be other etiologies for CFS. It is also possible that XMRV is a passenger virus whose replication is activated (and it is therefore detectable) more often in CFS patients than in healthy people. What could be the reason(s) for such activation? It could be weakened innate immunity due to the low activity variant of RNAse L. CFS patients, just like those prone to prostrate cancer, carry this gene variant more often than healthy people.

The Science study also reports XMRV in the blood of 8 of 213 healthy persons. This 3.7% positivity also raises various issues Are these people able to control XMRV more effectively? What about the RNAse L variant in these persons? This also shows that XMRV is far more prevalent than previously believed.

Where did XMRV come from? The DNA of XMRV from prostrate cancer patients shows >90% identity to xenotropic murine leukemia virus, a virus found in strains of wild and laboratory mice. Mice produce low levels of this virus, which does not reinfect mouse tissues, hence called xenotropic - a virus that can grow in a species other than its origin. It is possible that XMRV jumped from mice to humans, and unlike in mice, where the virus is in equilibrium with its host, it is still evolving in humans, and is therefore associated with some clinical syndromes.

XMRV is found in the blood of CFS patients. It can potentially be transmitted through transfusion, intravenous drug use and other routes involving blood/blood cells. Whether it can transmit by other routes will depend upon where else it is found in humans. But transmission studies have not yet been done.

Is there an association between CFS and prostrate cancer? These studies are suggestive, but more direct studies are required.

These studies raise interesting questions, which will keep the field busy for many years to come.

References:
Urisman A, et al (2006). Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathogens, 2 (3) PMID: 16609730
Lombardi V, et al (2009). Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science DOI: 10.1126/science.1179052