Another Retrovirus in Chronic Fatigue Syndrome

Is chronic fatigue syndrome (CFS) caused by a retrovirus? The answer to this question requires more investigation, but a study published this week found that 86.5% of the 37 patients tested appear to be infected with a murine leukemia virus (MLV).¹ In comparison, the MLV-related retrovirus was found in 6.8% in a general population of 44 blood donors.

The lead authors Shyh-Ching Lo, Ph.D., at the FDA and Harvey Alter, Ph.D., at the NIH, are two highly acclaimed virologists. In addition, Harvard’s CFS expert Anthony Komaroff, M.D., provided the majority of the patient blood samples and his track record for being thorough leaves no question that the samples used for the study represent the modern-day person with CFS. However, even with a skilled team, replication of these findings on a larger scale are urgently needed.

Last year a U.S. team reported that 68% of CFS patients had DNA evidence of a xenotropic MLV-related virus (XMRV).² They also reported XMRV was present in 2.7% of healthy blood donors. After the initial news of the XMRV, four other studies failed to find it in blood samples from CFS patients. So what exactly does this latest published finding mean?

Both XMRV and MLV are retroviruses that originate from mice (e.g., murine in their name means “from mouse”). Xenotropic means the virus has evolved to the point where it can no longer go back to infect mice and must reside in humans. The most recently detected virus appears capable of infecting both mice and humans, meaning it is polytropic (infecting more than one species) rather than xenotropic.

The ability of the MLV-related virus to live inside mice and humans means that the gene sequences controlling how it infects a host would have to differ from that found in the XMRV. As it turns out, Lo and Alter report that the section regulating how each virus infects a host does differ between the MLV-related virus and XMRV. So these are different–but related–viruses with genetic material that overlaps by 97%.

In the mid-1990s, it was hypothesized that CFS was caused by mycoplasmal infections (mycoplasma are literally miniature bacteria that might have easily escaped detection by standard lab tests). The 37 CFS blood samples from this study were frozen and used for the recent study by Lo and Alter.

Twenty-five of the patients were diagnosed by Komaroff and the remaining 12 from nearby physicians in private practice. Of the 25 CFS patients diagnosed by Komaroff, 24 (96 percent) tested positive for the MLV-related virus. In addition, he located eight of his 25 subjects whose blood was donated 15 years ago to get fresh blood earlier this year to analyze for the presence of the virus.

Seven of the eight “fresh blood” samples from the CFS patients tested positive for the MLV-related virus. However, they showed significant variation from the gene sequences detected from the blood drawn 15 years earlier. This is what would be expected from a retrovirus because they continue to evolve over time. If Lo and Alter had falsely identified a contaminant instead of a retrovirus, its gene structure would have remained the same. In fact, three closely related structures of the MLV-related virus were actually found in the CFS patients, which also reinforces the concept that this is a retroviral and not some other type of viral infection.

Due to the ever evolving nature of retroviruses, you may wonder how these infectious agents can be found and identified with a shred of confidence. Virologists use a number of probes that can detect short gene sequences believed to be specific for identifying various parts of the viral structure. The entire gene sequences of a retrovirus do not change, so if the multiple probes can detect enough matches, even an evolved retrovirus can be found. An analogy might be fingerprint analysis in which only seven points provides a match.

What does this all mean? Even Lo and Alter were quick to point out that while they found strong evidence of the MLV-related virus, they did not actually culture the agent. This would offer definitive proof that the retrovirus resides in CFS patients. Also, until much larger studies are done, the authors state that their 86.5% prevalence of the virus may not apply to CFS patients in the general population.

“Even if subsequent studies confirm an association between MLV-like viruses and CFS, that will not establish a causal role for these viruses in the pathogenesis of this illness,” write the authors. “For example, such a high frequency of infections with MLV-related viruses in patients with CFS could reflect an increased susceptibility to viral infections due to an underlying CFS-related immune dysfunction, rather than a primary role for these viruses in the pathogenesis of CFS.”

Whether the retrovirus is the cause of CFS or an opportunistic agent that takes advantage of people with a compromised immune system, this report by Lo and Alter is bound to draw more attention and research dollars to investigate the CFS-viral link. Given the high overlap between CFS and fibromyalgia, people with this latter diagnosis should also stay tuned for future studies on this retroviral connection as well.

1. Lo SC, et al. PNAS [Epub ahead of print] August 23, 2010.
2. Lombardi VC, et al. Science 326:585-589, 2009.