Discovery of XMRV retrovirus in chronic fatigue syndrome

[Guest guest]

Published Online October 8, 2009

Science DOI: 10.1126/science.1179052 Science Express Index

Reports

Submitted on July 14, 2009

Accepted on August 31, 2009

Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with

Chronic Fatigue Syndrome

C. Lombardi 1 , Francis W. Ruscetti 2 , Jaydip Das Gupta 3, Max A. Pfost

1, S. Hagen 1, L. 1, K. Ruscetti 4, K.

Bagni 5, Cari Petrow-Sadowski 6, Bert Gold 2, Dean 2, H.

Silverman 3, Judy A. Mikovits 1*

1 Whittemore Institute, Reno, NV 89557, USA.

2 Laboratory of Experimental Immunology, National Cancer Institute-Frederick,

Frederick, MD 21701, USA.

3 Department of Cancer Biology, The Lerner Research Institute, The Cleveland

Clinic Foundation, Cleveland, OH 44106, USA.

4 Laboratory of Cancer Prevention, National Cancer Institute-Frederick,

Frederick, MD 21701, USA.

5 Advanced Technology Program, National Cancer Institute-Frederick, Frederick,

MD 21701, USA.

6 Basic Research Program, Scientific Applications International Corporation,

National Cancer Institute-Frederick, Frederick, MD 21701, USA.

* To whom correspondence should be addressed.

Judy A. Mikovits , E-mail: judym@...

These authors contributed equally to this work.

Chronic fatigue syndrome (CFS) is a debilitating disease of unknown etiology

that is estimated to affect 17 million people worldwide. Studying peripheral

blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a

human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), in

68 of 101 patients (67%) compared to 8 of 218 (3.7%) healthy controls. Cell

culture experiments revealed that patient-derived XMRV is infectious and that

both cell-associated and cell-free transmission of the virus are possible.

Secondary viral infections were established in uninfected primary lymphocytes

and indicator cell lines following exposure to activated PBMCs, B cells, T

cells, or plasma derived from CFS patients. These findings raise the possibility

that XMRV may be a contributing factor in the pathogene

WALL STREET JOURNAL

OCTOBER 8, 2009, 3:12 P.M. ET

Retrovirus Linked to Chronic-Fatigue Syndrome

By AMY DOCKSER MARCUS

Researchers have linked an infectious virus known to cause cancer in animals to

chronic-fatigue syndrome, a major discovery for sufferers of the condition and

one that concerned scientists for its potential public-health implications.

An estimated 17 million people world-wide suffer from chronic-fatigue syndrome,

a devastating condition about which there is little medical consensus. CFS is

characterized by debilitating fatigue and chronic pain, among other symptoms,

but diagnosis is generally made by ruling out other diseases, and there are no

specific treatments.

Many patients say they are told by doctors that their problems are

psychological, so a study showing a strong association between a virus and CFS

is likely to change the field.

But the significance of the finding, published Thursday in Science, extends far

beyond the community of people living with CFS. Researchers are just as

concerned about the finding that nearly 4% of healthy people used as controls in

the study were also infected with the virus, called XMRV. If larger studies

confirm these numbers, it could mean that as many as 10 million people in the

U.S. and hundreds of millions of people around the world are infected with a

virus that is already strongly associated with at least two diseases.

The study was done by researchers at the Whittemore Institute for

Neuro-Immune Disease in Reno, Nev., the National Cancer Institute and the

Cleveland Clinic.

In September, researchers at the University of Utah and Columbia University

Medical Center found XMRV in 27% of the prostate-cancer samples they examined.

That study also showed that 6% of the benign prostate samples had XMRV. The

chronic-fatigue study is the first to find live XMRV virus in humans.

Neither study conclusively shows that XMRV causes chronic-fatigue syndrome or

prostate cancer. But the National Cancer Institute was sufficiently concerned to

convene a closed-door workshop in July to discuss the public-health implications

of XMRV infection. " NCI is responding like it did in the early days of HIV, "

says Stuart Le Grice, head of the Center of Excellence in HIV/AIDS and cancer

virology at NCI and one of the organizers of the July workshop.

Like HIV, XMRV is a retrovirus, meaning once someone is infected, the virus

permanently remains in the body; either a person's immune system keeps it under

control or drugs are needed to treat it. The virus creates an underlying immune

deficiency, which might make people vulnerable to a range of diseases, said Judy

Mikovits of the Whittemore Institute and one of the lead authors on the

paper.

So far, XMRV, known fully as xenotropic murine leukemia virus-related virus,

doesn't appear to replicate as quickly as HIV does. Scientists also don't know

how XMRV is transmitted, but the infection was found in patients' blood samples,

raising the possibility that it could be transmitted through blood or bodily

fluids.

Dr. Le Grice of the NCI said the highest priority now was to quickly develop a

validated blood test or other assay that could be used in doctors' offices to

determine who has XMRV. At the workshop, participants also raised the issue of

protecting the nation's blood supply. Dr. Le Grice said there isn't enough

evidence yet to suggest that people with XMRV shouldn't be blood donors but that

determining how XMRV is transmitted was a critical issue. " A large effort is

under way to answer all these questions, " he said. " I do not want this to be

cause for panic. "

Although Thursday's scientific paper doesn't demonstrate conclusively that XMRV

is a cause of CFS, additional unpublished data make it a very strong

possibility. Dr. Mikovits said that using additional tests, the scientists

determined that more than 95% of the patients in the study are either infected

with live virus or are making antibodies that show their immune systems mounted

an attack against XMRV and now had the virus under control. " Just like you

cannot have AIDS without HIV, I believe you won't be able to find a case of

chronic-fatigue syndrome without XMRV, " Dr. Mikovits said.

At the July workshop, Dr. Mikovits also presented preliminary data showing that

20 patients of the 101 in the study have lymphoma, a rare form of cancer. The

link between XMRV and lymphoma is still being investigated, but it raised the

possibility that XMRV may be associated with other cancers in addition to

prostate cancer. NCI's Dr. Le Grice said studies will be launched to determine

whether XMRV is associated with other diseases. At the Whittemore

Institute, Dr. Mikovits said they also found XMRV in people with autism,

atypical multiple sclerosis and fibromyalgia.

The Science study was based on blood samples from a national repository at the

Whittemore Institute collected from doctors in cities where outbreaks

of chronic-fatigue syndrome occurred during the 1980s and '90s. One of the key

questions that the NCI's Dr. Le Grice says must now be answered is whether XMRV

shows up in large numbers of CFS patients all over the country.

Silverman, a professor at the Cleveland Clinic Lerner Research Institute

who is one of the co-authors of the study and one of the discoverers of the XMRV

virus, said he believes the virus began in mice and then spread to humans, and

that " in most cases, people's immune systems are probably able to control the

virus. " Researchers are already starting to test antiretroviral therapies

developed for AIDS to see if they are effective against XMRV.

The work on XMRV in chronic-fatigue patients initially was funded by Annette and

Harvey Whittemore and the University of Nevada, Reno. The Whittemores set up the

institute in 2006 after watching their daughter suffer from

chronic-fatigue syndrome for most of her life. They spent millions of their own

money to pay for administrative services, office space, lab equipment and

research operations. They were frustrated by the lack of government funding for

scientific research into the disease.

At their home in Reno, the Whittemores' daughter, Whittemore-Goad, 31

years old, used oxygen before speaking about the devastating toll CFS has taken

on her.

Ms. Whittemore-Goad says she was a regular school girl, playing sports and

involved in school activities, until the age of 10, when she became ill with a

monolike virus that she couldn't shake. She said doctors first told her parents

that the illness was psychological, that she had school phobia and was under

stress from her parents. " We kept searching for an answer, " says Ms.

Whittemore-Goad, who says lymph nodes in her groin were so painful that her

brothers and sisters used to have to carry her upstairs. She was diagnosed at

age 12 with chronic-fatigue syndrome.

Over the years, doctors have treated her symptoms, like intense headaches and

severe pain, but the illness persists. She has had her gallbladder, spleen, and

appendix removed because they became infected. She tried an experimental drug

that she says gave her relief for years, but she then started experiencing side

effects and had to stop taking it. Recently the illness has become worse; she

began suffering seizures and can no longer drive.

Sitting on the couch next to her husband, whom she married six months ago after

meeting, Ms. Whittemore-Goad says the news that she is infected with XMRV " made

everything that has happened to me make sense. " Goad, her husband, said he

felt relieved knowing " now we can find a way to treat and hopefully cure it. "

For both of them, the discovery of the virus is life-changing. There are more

than 10 families in the group where family members also tested positive for

XMRV. Members of the Whittemore family are now being tested.

Write to Amy Dockser Marcus at amy.marcus@...

REUTERS

Study isolates virus in chronic fatigue sufferers

Thu Oct 8, 2009 2:00pm EDT

* Virus found in 67 percent of chronic fatigue patients

* Findings show link to CSF, not proof of causation

* Discovery a major step toward treatment options

By

WASHINGTON, Oct 8 (Reuters) - A virus linked to prostate cancer also appears to

play a role in chronic fatigue syndrome, according to research that could lead

to the first drug treatments for a mysterious disorder that affects 17 million

people worldwide.

Researchers found the virus, known as XMRV, in the blood of 68 out of 101

chronic fatigue syndrome patients. The same virus showed up in only 8 of 218

healthy people, they reported on Thursday in the journal Science.

Judy Mikovits of the Whittemore Institute in Nevada and colleagues at

the National Cancer Institute and the Cleveland Clinic emphasized that the

finding only shows a link between the virus and chronic fatigue syndrome, or

CFS, and does not prove that the pathogen causes the disorder.

Much more study would be necessary to show a direct link, but Mikovits said the

study offers hope that CFS sufferers might gain relief from a cocktail of drugs

designed to fight AIDS, cancer and inflammation.

" You can imagine a number of combination therapies that could be quite effective

and could at least be used in clinical trials right away, " Mikovits said in a

telephone interview.

She said AIDS drugs such as non-nucleoside reverse transcriptase inhibitors and

integrase inhibitors as well as nonsteroidal anti-inflammatory drugs and

cancer-fighting proteasome inhibitors could be tested as potential treatments

for CFS.

Takeda Pharmaceutical Co Ltd (4502.T: Quote, Profile, Research, Stock Buzz)

makes a cancer drug called Velcade that is a proteasome inhibitor, although

there are no reports that it has been tested against XMRV.

INCAPACITATING FATIGUE

CFS impairs the immune system and causes incapacitating fatigue, according to

the U.S. Centers for Disease Control and Prevention. Sufferers can also

experience memory loss, problems with concentration, joint and muscle pain,

headaches, tender lymph nodes and sore throats.

Symptoms last at least six months and can be as disabling as multiple sclerosis

or rheumatoid arthritis, the CDC said.

But Mikovits said there is currently no treatment for CFS aside from cognitive

behavioral therapy to help patients cope with the disorder's crippling effects.

The XMRV virus is a retrovirus, like the HIV virus that causes AIDS. As with all

viruses, a retrovirus copies its genetic code into the DNA of its host but uses

RNA -- a working form of DNA -- instead of using DNA to do so.

Known formally as xenotropic murine leukemia virus-related virus, XMRV has also

been found in some prostate tumors and is also known to cause leukemia and

tumors in animals. [iD:nN07209255]

Mikovits' team said further research must now determine whether XMRV directly

causes CFS, is just a passenger virus in the suppressed immune systems of

sufferers or a pathogen that acts in concert with other viruses that have been

implicated in the disorder by previous research.

" Conceivably these viruses could be co-factors in pathogenesis, as is the case

for HIV-mediated disease, where co-infecting pathogens play an important role, "

the report said.

Because 3.7 percent of the healthy test population tested positive for XMRV, the

researchers said several million otherwise healthy people in the United States

could be infected with it. (Editing by Maggie Fox and Vicki )

THE WASHINGTON POST

Virus Associated With Chronic Fatigue Syndrome

Scientists have found evidence that a virus may play a role in chronic fatigue

syndrome.

C. Lombardi of the Whittemore Institute in Reno, Nev., and

scientists elsewhere studied 101 patients with chronic fatigue syndrome, a

baffling, debilitating and controversial condition that affects an estimated 17

million people worldwide. They discovered that 68 of the patients -- 67 percent

-- had a virus in their blood known as the xenotropic murine leukemia

virus-related virus or XMRV. Only eight of 218 similar subjects who did not have

chronic fatigue syndrome -- 3.7 percent -- had the virus in their blood, the

researchers report in a paper published online Thursday by the journal Science.

Further studies showed that the virus is indeed infectious, and can " provoke "

the immune system to respond.

The researchers cautioned that the findings far from prove that the virus causes

chronic fatigue. It may be just part of the picture. But they suggest that the

virus may at least contribute to the development of the disorder. This isn't the

first time a virus has been associated with the condition. Previous research has

suggested that some herpes viruses and other viruses may also play a role.

In an article accompanying the research, Coffin of Tufts University in

Boston and Stoye of the National Institute for Medical Research in

London agreed. They noted that there are many unanswered questions about the

virus, including how it is transmitted. But if the findings are representative

of what's going on in the general public, perhaps 10 million Americans and

hundreds of millions of people worldwide might be infected with the virus, which

could turn out to be playing a role in a variety of diseases. The virus

previously was found in some patients with prostate cancer.

By Rob Stein | October 8, 2009; 2:00 PM ET |

NPR

Virus Linked To Chronic Fatigue Syndrome

by Jon Hamilton

October 8, 2009

Scientists have uncovered a strong link between an unusual virus and chronic

fatigue syndrome, which affects more than 1 million people in the United States.

Researchers found that two-thirds of people with chronic fatigue are infected

with a retrovirus called XMRV, according to a new study in the journal Science

Express. XMRV has also been found in the tumors of some prostate cancer

patients.

Scientists say it's too soon to say whether XMRV actually causes chronic

fatigue.

People with the syndrome feel tired even after a good night's sleep. Many also

have debilitating pain in their muscles or joints, trouble concentrating and

immune problems.

The new study compared blood samples from 101 chronic fatigue patients with

samples from 218 healthy people. About 67 percent of the sick people had XMRV,

compared with fewer than 4 percent of healthy people.

Understanding The Retrovirus

XMRV and other retroviruses are known to infect immune cells. XMRV has been

found in some prostate tumors. It's also related to a retrovirus that causes

cancer in animals.

The best-known retrovirus is HIV. But scientists say XMRV is simpler, and not a

close relative.

In people, XMRV could explain " the entire spectrum of symptoms that have come to

be known as chronic fatigue syndrome, " says Judy Mikovits, one of the study's

authors and research director of the Whittemore Institute at the

University of Nevada, Reno.

But scientists have pointed to viruses as a cause of chronic fatigue before and

been wrong.

" This is a very striking initial finding, but it is only an initial finding, "

says Coffin, a molecular biologist from Tufts University who was not

involved in the study. He co-authored a companion piece about the finding in

Science Express.

Researchers have suspected for a long time that chronic fatigue might be caused

by a virus.

One reason for that suspicion is that many people get the condition after a

flu-like illness, says Mikovits. " They get very bad flu-like symptoms and

essentially never recover, " she says.

Most viruses don't survive long in the body. But retroviruses are one type that

lingers. HIV, for example, is a retrovirus that infects people for a lifetime.

So when scientists found XMRV in people a couple of years ago, Mikovits thought

there might be a connection to chronic fatigue, which also tends to last a

lifetime.

She was in a position to find out. After many years at the National Institutes

of Health, she'd come to the Whittemore Institute, a place founded to

help people with chronic fatigue.

Mikovits worked with a team that began checking patients' blood for XMRV.

" We simply did a screen of the sickest of the sick of our patients because we

figured that would be where we would find the most virus, " she says. " And, lo

and behold, there it was. "

Tests also showed the virus was infectious and was provoking an immune response

in people with chronic fatigue.

Isolating The Cause

The finding is " the best news ever " for people with chronic fatigue, says

Annette Whittemore, one of the founders of the Whittemore Institute.

" We've always known there was something out there. Now we see its face, " she

says.

Whittemore has an adult daughter who has had chronic fatigue since she was 12.

She created the institute with Dr. , one of the first doctors to

identify people with the condition that later became known as chronic fatigue

syndrome.

Even though XMRV has not yet been shown to cause chronic fatigue syndrome, it

has characteristics that make it a likely suspect, experts say.

For one thing, it's a retrovirus.

" Retroviruses in general give rise to infections that persist indefinitely, "

says Coffin. Most other viruses are eliminated from the body.

Coffin says he's concerned by the finding that nearly 4 percent of healthy

people carried XMRV. That would mean 10 million people in the U.S. are infected.

Coffin says scientists need to find out whether the virus is causing health

problems other than chronic fatigue in any of these people.

For people who have chronic fatigue, the XMRV finding could lead to the first

treatments.

Antiviral drugs developed for people with HIV may also work against XMRV,

Mikovits says. The institute plans to begin testing that idea soon.

NATURENEWS

Published online 8 October 2009 | Nature | doi:10.1038/news.2009.983

Virus linked to chronic fatigue syndrome

Prostate cancer pathogen may be behind the disease once dubbed 'yuppie flu'.

Lizzie Buchen

A study on chronic fatigue syndrome (CFS) has linked the mysterious and

controversial disease to a recently discovered retrovirus. Just last month

researchers found the same virus to be associated with aggressive prostate

tumours.

CFS is marked by debilitating exhaustion and often an array of other symptoms,

including memory and concentration problems and painful muscles and joints. The

underlying cause of the disease is unknown; it is diagnosed only when other

physical and psychiatric diseases have been excluded. Though the disease's

nebulous nature originally drew scepticism from both doctors and the general

public, most of the medical community now perceives it as a serious — if poorly

defined — disease.

Now Judy Mikovits of the Whittemore Institute for Neuro-Immune Disease

in Reno, Nevada, and her colleagues think they have discovered a potential

pathogenic link to CFS. In patients with the disease from different parts of the

United States, 67% were infected with a retrovirus known as XMRV. Less than 4%

of controls carried the virus.

" I can't wait to be able to tell my patients, " says Mikovits, who is also the

vice president of drug development for Genyous Biomed in , Nevada.

" It's going to knock their socks off. They've had such a stigma. People have

just assumed they were just complainers who didn't handle stress well. "

Prostate puzzle

CFS researchers have long had their eyes on retroviruses. A number of the

symptoms, including fatigue and cognitive dysfunction, can occur when the immune

system is dealing with a viral infection, and the disease is often preceded by a

flu-like illness. Although a number of retroviruses have been hypothesized to

play a role in CFS, none has ever been confirmed.

About three years ago Silverman, a biologist at the Cleveland Clinic

Foundation in Ohio and a coauthor of the new study, discovered a previously

unknown retrovirus, XMRV, while searching for a pathogen that might contribute

to prostate cancer. The retrovirus was very similar to MLV, a group of viruses

that can cause cancer and neurological and immunological diseases in mice.

Silverman found XMRV in a subset of prostate tumours, and more recent research

found a stronger correlation between XMRV and aggressive prostate tumours1,2.

Mikovits asked Silverman to analyze the blood samples of 101 CFS patients and

218 healthy controls. The authors detected XMRV DNA in the immune cells of 67%

of the CFS patients but in only 3.7% of healthy controls. The authors also

showed that the virus was able to spread from infected immune cells to cultured

prostate cancer cells and that the virus's DNA sequence was more than 99%

similar to the sequence of the virus associated with prostate cancer. The

findings were published in Science3.

" It's scary, " says Mikovits. " But it's cool. Hopefully this will finally make

people change their attitudes to this disease. "

Mikovits believes the association may be even stronger than the present work

indicates. DNA sequencing only picks up active infections, she says, so she

wants to study CFS exposure to the virus more broadly. In an unpublished

investigation, she and her colleagues analyzed blood cells in about 330 CFS

patients and found that more than 95% expressed antibodies to XMRV, whereas

about 4% of healthy controls did.

Controversial connection

Although Mikovits acknowledges that it's premature to suggest a causal link

between XMRV and CFS, she thinks it makes sense. Chronic XMRV infection in

immune cells could cause them to churn out inflammatory cytokines, which are

observed in some CFS patients, she says. Mikovits also points out that the MLV

coat protein can disrupt red blood cells in mice, leading to low blood oxygen

levels.

Reeves, principal investigator for the Centers for Disease Control and

Prevention (CDC)'s CFS public health research programme, says the findings are

" unexpected and surprising " and that it is " almost unheard of to find an

association of this magnitude between an infectious agent and a well-defined

chronic disease, much less an illness like CFS " .

But Reeves is cautious. " Until the work is independently verified, the report

represents a single pilot study, " he says. According to Reeves, the CDC is

already trying to replicate these findings. He also notes that CFS is a

heterogeneous disease and likely arises from a combination of many factors.

XMRV presents its own puzzle. Coffin, a virologist at Tufts University in

Boston who has studied MLV, points out that the virus's prevalence in healthy

controls " is, in some ways, an equally striking result " .

" It's highly preliminary, but if it's in fact representative, then there are 10

million Americans with this infection, which is very similar to MLV and is now

linked to two important diseases, " says Coffin. " There's a lot we don't know,

including whether XMRV causes disease, but that's always the case when the first

paper, like this one, comes out. "

• References

1. Schlaberg, R. et al. Proc. Natl Acad. Sci. USA 106, 16351– 16356 (2009).

2. Urisman, A. et al. PLoS Pathogens 2, e25 (2006).

3. Lombardi, V. C. et al. Science doi:10.1126/science.117052 (2009).