Retrovirus Linked to Chronic Fatigue Syndrome

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http://www.scientificamerican.com/article.cfm?id=chronic-fatigue-syndrome-retrovirus&sc=DD_20091009

Retrovirus Linked to Chronic Fatigue Syndrome, Could Aid in Diagnosis

Recently implicated in some severe prostate cancer patients, the retrovirus XMRV has now been found in many with chronic fatigue--changing the landscape for diagnosis and possible treatment

By Katherine Harmon
OVERTAKING CHRONIC FATIGUE: An electron micrograph shows the XMRV retrovrius in the blood of a patient with chronic fatigue syndrome.
WHITTENMORE PETERSON INSTITUTE


More so than many illnesses, chronic fatigue syndrome (CFS) frustrates those who suffer from it and those close to them, due to its nebulous assembly of symptoms, along with continued controversies over its etiology, diagnosis, treatment and even its nomenclature. Now, the discovery of a familiar retrovirus in many CFS patients could bring new energy to the field—and fresh hope for more specific medical care.

Chronic fatigue is in part a misnomer. The syndrome often has more to do with immune system abnormalities than pervasive tiredness—although the two can go hand in hand. The symptoms range from exhaustion to muscle pain, giving CFS a reputation among some as a "wastebasket diagnosis". The slipperiness of the syndrome is in part because "it's diagnosed based on exclusion," says Judy Mikovits, director of research at the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, Nev., and co-author of research on the retrovirus findings published online today in Science. Doctors often apply the label if no other explanation can be found for a patient's symptoms, which may be part of the reason it seems to pop up in everyone from overworked career women to continually sick children.

Roughly 17 million people worldwide are thought to have CFS, but given current diagnosis methods, the true number could be much higher or lower. Having a specific virus to look for would make for much more robust tests and possibly even be a step toward treatment. Mikovits's team thinks they have found just such a candidate.

The xenotropic murine leukemia virus–related virus (XMRV), a type of gammaretrovirus, has recently been linked to strong cases of prostate cancer. Like CFS, this cancer involves changes in an antiviral enzyme (RNase L). The prostate cancer discovery, described last month by Ila Singh, an associate professor of pathology at the University of Utah in Salt Lake City, et al. in the Proceedings of the National Academy of Sciences (PNAS), along with a traditionally high incidence of cancer in CFS patients, got Mikovits and her team thinking: Would they find the same retrovirus in people with CFS?

After analyzing biological samples from more than 100 CFS patients for the retrovirus, two thirds of them were found to test positive for the virus—compared with 3.7 percent of 218 healthy volunteers who were screened.

To find the retrovirus, Mikovits and her team studied documented cases, such as CFS outbreaks in a symphony orchestra in North Carolina and in Incline Village, Nev. "We found the virus in the same proportion in every outbreak," she says. But how are people getting this retrovirus? "Ila's work shows that everyone's susceptible," Mikovits says of the PNAS paper by Singh that illustrates the link between prostate cancer and XMRV and shows that the virus is not linked to a genetic mutation.

Experiments in Mikovits's lab proved that the retrovirus can be transmitted via blood by infecting healthy cells drawn from volunteers with material from XMRV-positive CFS patients. Mikovits hopes to soon have a better understanding of how the virus might be transferred in the real world, especially among families. If it, for instance, is like human T-lymphotropic virus type 1 (HTLV-1), it may be communicable through breast milk or if it's like a herpes virus that is common in CFS, it may be passed along to offspring.

Precisely how this virus is related to chronic fatigue, however, remains a mystery. One of the problems with tracking down CFS is that it may not be a single ailment. "We think that the problem is that CFS is a collection of many, many different diseases even though it has similar symptoms," says Brigitte Huber, a professor of pathology at Tufts University's Sackler School of Graduate Biomedical Sciences in Boston. She and others suspect that the retrovirus may be unleashing other underlying conditions and viruses in the body.

"This new retrovirus may be able, through infecting human cells, [to] induce a transcription of an endogenous virus," says Huber, who has been studying the presence of an ancient retrovirus (HERV-K1 dormant in most people but active in patients with CFS and multiple sclerosis. "We've already shown that Epstein-Barr virus can do exactly this."

Even in their testing for the XMRV retrovirus, Mikovits says, "We could see a human endogenous virus at the same time" as XMRV. "There are a number of old diseases that seem to be rising at an infectious rate," she says. Although this background noise of various viruses may be difficult to sort though, it brings clues to help researchers find the root cause of CFS. "It's possible, downstream, that this will all feed into the same mechanism," Huber says.



Even before the precise mechanisms are found, work toward finding treatment proceeds. Animal model testing is already underway, and Mikovits notes that her team is looking into some reverse transcriptase inhibitors that have already been approved by the U.S. Food and Drug Administration for other uses.

"Now we have a drug target and a marker," Mikovits says. "If we treat them with a drug and they get better, we win."

In the meantime, her team has been making quick strides toward a simple diagnostic test that doctors could use to check for the virus. Tests have been running smoothly in the lab, she notes, with some diagnostics companies already interested in the technology. She predicts a test will be available in less than six months. Mikovits adds that she is "excited that we will actually have some causes…rather than just building a better wheelchair."

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http://www.nytimes.com/2009/10/13/he...ewanted=2&_r=1

Is a Virus the Cause of Fatigue Syndrome?

Candice Towell for The New York Times
Andrea Whittemore-Goad, 31, was diagnosed with chronic-fatigue syndrome when she was 12.

By DENISE GRADY
Published: October 12, 2009
Could a virus be the cause of chronic fatigue syndrome?

A study published last week in the journal Science suggested that might be the case, reporting that many patients who had the syndrome were infected with a recently discovered virus.
Chronic fatigue syndrome has long been a medical mystery and the subject of debate, sometimes bitter, among doctors, researchers and patients. It affects at least one million Americans, causing extreme fatigue, muscle and joint pain, sleep problems, difficulty concentrating and other symptoms. Its cause is unknown, symptoms can last for years and there is no effective treatment. Researchers disagree about whether it is one disease or a collection of symptoms that may have different causes in different patients. It has sometimes been stigmatized as more mental than physical, with patients labeled neurotic, depressed or hypochondriacal. Many patients find even the name of the disorder offensive, a not-so-subtle hint that it is not a real disease.
The new report has intrigued scientists, been seen as vindication by some patients and inspired hope for a treatment.
“I just feel like the whole future has changed for us,” said Anne Ursu, 36, a writer living in Cleveland who has had the syndrome in the past.
But the new study is not conclusive, and a great deal of work remains to be done to find out whether the new virus really does play a role. Just detecting it in patients does not prove it is what made them sick; people with the syndrome may have some other underlying problem that makes them susceptible to the virus, which could be just a passenger in their cells.
Even so, thousands of patients have already contacted scientists, asking to be tested, said Dr. Judy Mikovits, the first author of the study and the research director at the Whittemore Peterson Institute in Reno, a research center created by the parents of a woman who has the syndrome. Dr. Mikovits said she expected a test to become available “within weeks.”
The new suspect is a xenotropic murine leukemia virus-related virus, or XMRV, which probably descended from a group of viruses that cause cancer in mice. How or when XMRV found its way into humans is unknown. But it has also been linked to cancer in people: it was first identified three years ago, in prostate cancer, and later detected in about one-quarter of biopsies from men with that disease (and in only 6 percent of benign biopsies). It is a retrovirus, from the same notorious family that causes AIDS and leukemia in people.
Dr. Mikovits and researchers from the National Cancer Institute and the Cleveland Clinic reported in Science that 68 of 101 patients with chronic fatigue syndrome, or 67 percent, were infected with XMRV, compared with only 3.7 percent of 218 healthy control subjects. Further testing after the paper was written found the virus in nearly 98 percent of about 300 patients with the syndrome, Dr. Mikovits said.
She said she believed that the virus would eventually be found in every patient with chronic fatigue syndrome. XMRV affects the immune system, can probably cause a variety of illnesses and may join forces with other viruses to bring on the syndrome, she said.
The study received a mixed review from Dr. William C. Reeves, who directs public health research on the syndrome at the Centers for Disease Control and Prevention. He called the research exciting but preliminary, and said he was surprised that a prestigious journal like Science had published it, because the researchers did not state the ages or sex of the patients and controls, or describe the duration of the illness or how it came on.
“If I don’t know the nature of the cases and controls, I can’t interpret the findings,” Dr. Reeves said.
“We and others are looking at our own specimens and trying to confirm it,” he said, adding, “If we validate it, great. My expectation is that we will not.”
He noted that there had been false starts before, including a study in the 1990s linking the syndrome to another retrovirus, which could not be confirmed by later research.
Many patients and a community of doctors and researchers who specialize in the syndrome take issue with the disease centers’ approach to the illness and the way it defines who is affected. They claim that the C.D.C. includes people whose problems are purely psychiatric, muddying the water and confounding efforts to find a physical cause.
Frustration with the lack of answers led Annette and Harvey Whittemore, whose 31-year-old daughter has had the syndrome for 20 years, to spend several million dollars to set up a research institute at the University of Nevada in Reno in 2004, and to hire Dr. Mikovits to direct it.
Mrs. Whittemore said she had long believed that the syndrome was an infectious disease, but that scientists had rejected the idea.
She finally decided, she said, “if there was a place of our own where we could find the answers, we could do it more quickly.”
Dr. William Schaffner, an infectious disease expert at Vanderbilt University, said that the notion of a lingering viral infection was plausible. He said that although some patients claiming to have the syndrome seemed more likely to have a psychological problem, others seemed to have a physical illness.
“There is a group who are young, healthy, active and engaged, and all of a sudden they are laid low by something,” Dr. Schaffner said. “Everyone tells the physicians these are people who are functional and productive, and this is totally out of character. They are frustrated and often quite disheartened. You feel that medical science hasn’t caught up with their illness yet.”
To determine whether XMRV is to blame, more studies are needed, said Dr. John Coffin, a professor of molecular biology and microbiology at Tufts University. It would help to find an animal model, he said, and to look at stored blood samples to find out if there were people who became ill some set amount of time after contracting the virus. If antiviral drugs make patients improve, that will also help make the case against the virus, he said.
The National Cancer Institute is taking XMRV seriously, said Dr. Stuart Le Grice, head of its Center of Excellence in HIV/AIDS and Cancer Virology.
He said health officials became especially concerned last spring when several research teams looking at prostate cancer reported finding XMRV in 3 percent to 4 percent of blood samples from healthy people in control groups. That could translate into 10 million American being infected with a newly discovered, poorly understood retrovirus that has already been linked to two diseases.
“Any virus at that level is obviously cause for concern,” Dr. Le Grice said, adding that it was important to find out if the virus was associated with any more diseases, and how closely.
He said that just carrying the virus did not necessarily mean a person was at high risk for disease, noting that people may harbor other viruses that will never harm them. The immune system probably keeps the viruses in check.
But he asked: “If it is a problem, how well can we diagnose it and how well can we treat it?”
Even though antiretroviral drugs have already been developed to treat H.I.V. infection, he said this virus was different and might need its own line of drugs.

Continued next page

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He said more studies were needed to find out how common the virus is and how it is being transmitted. It is not known whether people can catch the disease from mice, or can infect one another. Retroviruses are often spread by blood and bodily fluids.
“How significant a risk is this to blood banks?” Dr. Le Grice asked. “Do we need to consider large-scale screening in blood banks?”
He said the institute would be working to develop reliable diagnostic tests.
Dr. Le Grice emphasized that there is no evidence that the virus is spreading through the population.
“I don’t want to scare anyone at the moment,” he said.

I don't know about anyone else, but I am very disturbed about the CDC's reaction to the study. How can they "expect that the study will not be validated"? Is the outcome of their own "study" predetermined the way another study most likely is (the one due out next month)?
Is it a piece of the puzzle that they do not want to surface?
The plot thickens...

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XMRV - The Puppet Master? by Cort Johnson

XMRV and ME/CFS: the Puppetmaster
The Puppet Master?


Dr. Bell speculates that XMRV could be a kind of 'puppet master' that allows other infections such as EBV or HHV6 or Lyme or enterovirus to become exacerbated. Dr. Coffin echoed this idea in his article "A New Virus For Old Diseases". Dr. Huber, a researcher studying endogenous viral elements in ME/CFS has suggested that XMRV could unlock endogenous retroviral elements in our DNA. Dr. Cheney stated that based on the limited results from his clinic it could XMRV could be a factor in autism and ADHD and wonders about arthrits, asthma and cancer. Dr. Mikovits has reported that XMRV can be found in autism and 'atypical MS' patients. Its all a bit overwhelming.
Dig Deeper! - Dr. Bell on XMRV
Dig Deeper! A New Virus For Old Diseases (see second post)

Autism - The Nevada Autism Commission revealed that 40% of a 'small group of children' with autism tested postive for XMRV. Dr. Mikovits verified this stating " we have actually done some of these studies (in ASD children) and found the virus in a significant number of samples that we have tested for. It could be linked to a number of neuro-immune diseases, including autism" but that at best it would be one several factor that contributed to the disorder. Dr. Mikovits also speculated that the virus could be a factor in vaccination triggered autism (see below). </SPAN> Dig Deeper! Is Autism Associated with a Viral Infection (Huffington Post)
Infectious mononucleosis - No one's mentioned a key factor in many patients journey - infectious mononucleosis. Could an XMRV infection be a risk factor for getting infectious mononucleosis; ie. do people who get the more severe form of Epstein-Barr virus infection (infectious mononucleosis) rather than the less severe form (mild cold) tend to carry the XMRV virus?
The Dubbo and Taylor studies could show that XMRV is not restricted to the ME/CFS patients. It turns out that if you have infectious mononucleosis you also have an increased risk of coming down with multiple sclerosis and the WPI has already reported finding XMRV in 'atypical' MS patients. Could the scenario go MRV infection in childhood = increased risk of infectious mononucleosis = increased risk of ME/CFS or multiple sclerosis?
Dig Deeper!: the Dubbo Studies
Other Diseases - ME/CFS is not the only disease with disabling fatigue, cognition problems, sleep problems, etc. Besides related diseases like fibromyalgia there are also a number of diseases which don't appear to be related to chronic fatigue syndrome at all but which have subsets of patients who look very much like chronic fatigue syndrome patients. A significant subset of post-cancer patients, post ICU patients, post heart surgery patients, patients with liver disease and multiple sclerosis patients have a very CFS-like condition. Researchers have speculated that they are in fact chronic fatigue syndrome showing up in other diseases.
What these conditions share is a stress trigger; whether it comes in the form of an infection, a physical trauma ( fibromyalgia), cancer treatment, surgery, etc. This, of course that the stress response plays a critical role in the development of this illness. Note that this does not at all conflict with any of the statements that Dr. Mikovits has made regarding possible triggers for XMRV activation; two of them she mentioned - cortisol and inflammatory cytokine levels - are increased during the stress response. Could the CFS-like post-cancer, post-ICU, MS patients, etc. patients be harboring the XMRV virus? The possibilites for this virus - at this very early stage when we don't know much - appear to go on and on.
Why might retroviruses at least theoretically be able to trigger so much disturbance? Because we're pretty much stuck with them; instead of eventually getting killed off in the body like other viruses they tend to linger in the body - i.e. they are chronic - and they can be pretty good (aka HIV) at creating a condition which other pathogens can take advantage of. Let's not forget , though, that most retroviruses are completely harmless.. In fact our DNA is studded with the remnants of old retroviruses that have embedded themselves in our genome.
Dissenting Views - there is also some reason to believe that this virus might not be some sort of 'Puppet Master' that turns on a 'viral cascade' in patients. A study by Dr. Nicholson found tthat one virus does not appear to open the door to another virus in ME/CFS patients. Instead ME/CFS patients as a group tend to have one or another opportunistic virus. Dr. Natelson reports finding very, very few viruses in the patients that he sees.
Reports from the WPI, on the other hand, mention finding dozens of different types of viral fragments in the sophisticated tests in chronic fatigue syndrome patients and very few in controls. Is technology the difference here? Or are these physicians looking at different types of patients. Clearly we're still in the early stages of getting a clear picture of the viral component in this disorder.
Triggering Factors - Since we've seen that healthy people can carry this virus it's clear that XMRV doesn't necessarily cause disease. If it does turn out to be a key factor in chronic fatigue syndrome and other neuro- immune illnesses something's going to have to either turn it on or exacerbate its effects when it is active. What could turn XMRV from a rather innocuous bystander into a big problem?
Cortisol - Dr. Mikovits has speculated that stress hormones like our friend cortisol, or inflammatory cytokines or vaccines could all concievably shift XMRV from a Dr. Hyde to a Dr. Jekyll-like state. Many studies have shown that low levels of cortisol are present in a significant portion of ME/CFS patients. (Dr. Holtorf argues that the most widely used cortisol tests under estimate the true prevalence of low cortisol in this disorder). Chronically low cortisol produces inflammation (immune activation) which Dr. Mikovits suggests could trigger XMRV replication.
Dig Deeper! Hypocortisolism and chronic fatigue syndrome (ME/CFS)
Inflammatory Cytokines - The Dubbo studies suggest that cytokines are a triggering factor in chronic fatigue syndrome. These studies tried to determine how an infection turned into chronic fatigue syndrome. They found that people who had high inflammatory cytokine levels early in their illness tended to get chronic fatigue syndrome. Those people who didn't have the high inflammatory cytokine levels tended to recover.
Two prospective studies - the Dubbo studies and Renee Taylors recent study - have followed people as they came down with ME/CFS following an infection. Both presumably have blood samples they can test. These studies show that about 10% of infectious mononucleosis patients come down with postviral fatigue and a smaller percentage come down with chronic fatigue syndrome. Hopefully they are now testing their samples to see if the virus was restricted to the patients who later became ill with chronic fatigue syndrome.
Dig Deeper! the Dubbo Studies
Vaccines - given the viruses propensity for T and B cells it sounds like any kind of immune activation could - by causing T and B cells to replicate - resulting in increased replication of the virus and indeed Dr. Mikovits speculated that XMRV infection could play a role in the sometimes negative effects seen in vaccinations. (Annette Whittemore explained the WPI is not not advocating vaccine use in children. "We certainly are advocating vaccinations and how important those are to the well being of children" ).
Amyloids - Intriguingly given the preliminary evidence by Dr. Baraniuk that amyloidosis may play a role in chronic fatigue syndrome (ME/CFS) a 2009 study finding that ‘amyloidgenic fragments’ (SEVI) in prostate tissues appeared to ‘greatly increase’ XMRV infection. The authors noted that these fragments appeared to to create “an environment that provides a natural enhancer of (XMRV) infection.” Because there are several different types of amyloidic proteins a connection to Dr. Baraniuk's work is not clear. But because the virus can be carried in otherwise healthy people researchers will be looking for a 'triggering' factor that potentiates it. Could amyloid fragments in ME/CFS patients central nervous system be a contributing factor?
Dig Deeper! - Amyloids in Chronic Fatigue Syndrome (ME/CFS): A Biomarker in the Brain?
All is speculation at this point but should this virus turnout to play a major role in this disorder finding a 'triggering factor' will loom large particularly with regard to disease prevention. Retroviruses generally cannot be eliminated from the body but 30 years of HIV research has shown that can be controlled.
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