More Studies Find No XMRV in Chronic Fatigue Syndrome, HIV, or Hepatitis C

Kathleen Louden

October 14, 2010

October 14, 2010 — Another US study has failed to detect xenotropic murine leukemia virus–related virus (XMRV) in the blood of patients with chronic fatigue syndrome (CFS) or others with immune dysfunction, and investigators of a separate European study also found no evidence of this retrovirus in patients infected with HIV or hepatitis C virus. Both studies were published online October 11 and will appear in the November 15 print issue of the Journal of Infectious Diseases.

The negative findings come just weeks after publication of a study that was the second to find a murine leukemia-type virus in patients with CFS (Proc Natl Acad Sci USA. 2010;107[36]:15874-15879). That work used the same primers for polymerase chain reaction (PCR) amplification as used in the current US study, write the authors, led by Athe Tsibris, MD, from the Division of Infectious Diseases at Massachusetts General Hospital, Boston. Dr. Tsibris' group also reportedly used the same sensitive PCR methods as those of Lombardi and colleagues, who first reported XMRV in patients with CFS a year ago (Science. 2009;326:585-589).

"[Our finding] suggests that differences in PCR techniques from study to study do not explain the disparate results seen in XMRV studies of chronic fatigue syndrome," Dr. Tsibris said in a press release from the Infectious Diseases Society of America, publisher of the Journal of Infectious Diseases.

Dr. Tsibris and colleagues suggested that "geographical clustering of XMRV infection" could explain why other investigators found XMRV in patients with CFS. Their group, from Boston, tested peripheral blood mononuclear cells of 293 patients from academic hospitals. Of the participants, 23 met the Centers for Disease Control and Prevention revised case definition of CFS, and 95 were from a general cohort of patients who received medical care, which could have included healthy individuals seeking routine care, according to the authors.

All other participants had chronic conditions with altered immune function: 43 with HIV, 97 with rheumatoid arthritis, and 26 who had undergone solid-organ or hematopoietic stem cell transplantation.

The authors reported that they did not detect XMRV DNA in any samples. They did detect a mouse endogenous retroviral sequence in 1 participant's blood, but because they could not replicate that finding, the authors attributed it to contamination from an unidentified source.

Despite the number of studies that have been unable to find an association between XMRV and CFS, Dr. Tsibris told Medscape Medical News that it is too early to discount an association. "Additional next steps that would be helpful would be a standardized, cross-validated assay for XMRV detection in clinical samples," he said, "so that we can all at least agree on what a positive XMRV test actually is, and a blinded multilaboratory comparison of XMRV testing from CFS and control samples." The National Institutes of Health has plans for a study like this, according to Dr. Tsibris.

Virus May Not Be Transmitted via Blood

In the other study in the Journal of Infectious Diseases, UK and Swiss researchers aimed to determine whether patients with HIV type 1 or hepatitis C virus infection were at increased risk for XMRV infection. Led by Eleanor Barnes, MD, from Oxford University's Department of Clinical Medicine, United Kingdom, the authors tested 230 patients: 84 with chronic HIV infection, 79 with acute HIV infection, and 67 with hepatitis C virus infection.

After being unable to detect XMRV in plasma or peripheral blood mononuclear cells using PCR in any of the patients, the researchers retested 64 patients using a T-cell enzyme-linked immunospot (ELISPOT) assay. Of the 49 patients with acute HIV infection and 14 patients infected with hepatitis C virus whose peripheral blood samples were assayed, none were positive for XMRV, the authors report.

"Although [they are] widely used to detect T cells targeting retroviral peptides, this is the first time ELISPOT assays have been applied for the detection of responses to XMRV," the authors write. "Patient cells were responsive to other antigens, suggesting that the lack of responses simply reflects an absence of XMRV Gag-specific T cells in our cohort."

Given their findings, Dr. Barnes said in a press release that "if XMRV is a human pathogen, it is not enriched in the blood of patients with HIV or hepatitis C virus, and by implication it is unlikely to be spread through sexual or blood-borne routes in the United Kingdom and Western Europe."

The possibility that XMRV can be transmitted through blood arose after Lombardi and coworkers reported that they could secondarily transmit the virus from the blood cells and plasma of infected patients with CFS. This led the transfusion medicine organization AABB to recommend earlier this year that blood collection centers discourage people with a diagnosis of CFS or related disorder from donating blood or blood components.

A third study in the Journal of Infectious Diseases reported finding XMRV in patients with prostate cancer, as some other researchers have found.

Antiretroviral Therapy Use "Premature"

The conflicting results of the 3 studies led authors of an accompanying editorial to subtitle their commentary "Reach for a Scorecard, Not a Prescription Pad."

Mary Kearney, PhD, and Frank Maldarelli, PhD, MD, from the HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, point out in the editorial that valid detection of XMRV remains an ongoing problem. To resolve the issue, they suggest the following 5 steps:

  1. Standardize detection assays.

  2. Conduct prospective epidemiologic surveys.

  3. Share reagents and samples.

  4. Design "comprehensive and rigorous" phylogenetic sequence analysis.

  5. Develop "tractable animal models," including macaques. These models "will be necessary to dissect XMRV pathogenesis," the editorialists explain.

"Only when this is done in a rigorous fashion will it become clear what role XMRV or related viruses have in human disease," according to a journal press release.

Dr. Kearney and Dr. Maldarelli add that although antiretroviral therapy is effective against XMRV in vitro, current research shows that its usefulness in humans may be low.

"At this time, such an approach is premature and medically indefensible outside the secure oversight of a well-controlled clinical trial," the editorialists write. " 'Real world' coping with severe diseases like [CFS] and prostate cancer creates understandable desperation on the part of patients, caregivers, and health care professionals. Such pressures are not justification for testing of therapies in an uncontrolled manner," they conclude.

Dr. Tsibris has disclosed a grant from the National Institutes of Health but no relevant financial relationships. Dr. Barnes reports receiving financial support for her study from the Swiss National Science Foundation but no relevant financial relationships.

J Infect Dis. Published online October 11, 2010.

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