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New Data on Mouse Retroviruses Link to Prostate Cancer, Chronic Fatigue Syndrome

A set of studies published in the November 15, 2010 Journal of Infectious Diseases shed further light on associations between murine or mouse retroviruses and human disease. One study found xenotropic murine leukemia virus-related virus (XMRV) in normal and tumor tissue from men with prostate cancer. Two other studies in the same issue, however, did not see evidence of XMRV in people with chronic fatigue syndrome (CFS), blood-borne infections, or chronic immune suppression or activation, conflicting with prior findings. Experts urge more rigorous research and consistent methodology to help resolve such inconsistencies across studies.

Murine leukemia virus (MLV), xenotropic murine leukemia virus-related virus (XMRV), and similar retroviruses have been linked to a variety of human diseases. Like HIV, these viruses copy DNA from RNA and integrate their genetic material into human host cells. Some researchers have found that certain antiretroviral drugs used to treat HIV are also active against XMRV.

Several research teams have reported finding MLV and XMRV in people with prostate cancer, chronic fatigue, leukemia, and other conditions. A widely cited study by Judy Mikovits and colleagues published in Science in 2009, for example, showed that about two-thirds of people with CFS carried XMRV in their peripheral blood mononuclear cells (PBMCs), compared with only 4% of unaffected individuals. But other investigators have failed to find similar associations.

In the first of the current studies, Bryan Danielson, Jason Kimata, and colleagues from Baylor College of Medicine looked at the prevalence of XMRV in patients with prostate cancer and its association with the RNASEL R462Q polymorphism, or genetic variation, which is often present in men with aggressive prostate cancer.

The analysis included prostate tissue specimens from 144 men with prostate cancer in the southern U.S. Samples were screened for XMRV proviral DNA using nested polymerase chain reaction (PCR) specific for the env gene, and genotyped for R462Q using real time PCR.

The researchers detected XMRV in 22% of the patients' samples. Individuals were significantly more likely to test positive for XMRV in both tumor and normal tissue samples, rather than either type alone. The R462Q polymorphism was found at an allelic frequency of 0.33, but having detectable XMRV was not significantly correlated with R462Q or with clinical parameters of prostate cancer.

"The presence of XMRV in normal tissue suggests that infection may precede cancer onset," the study authors concluded, adding that the virus does not appear to specifically target cancer cells.

In the second study, Timothy Henrich, Athe Tsibris, and colleagues investigated the prevalence of XMRV among 293 people with various chronic immune suppression or immune activation conditions seen at academic hospitals in Boston. The study population included 32 patients with CFS, 97 people with rheumatoid arthritis, 43 HIV positive people, 26 patients with stem cell or solid organ transplants (who receive immunosuppressive therapy), and 95 people from a general cohort of patients seeking medical care.

In this analysis, XMRV DNA was not detected in any of the participants. "We found no association between XMRV and patients with chronic fatigue syndrome or chronic immunomodulatory conditions," the investigators concluded.

In the third study, Eleanor Barnes from Oxford University and colleagues looked for XMRV in 230 people with HIV or hepatitis C virus (HCV) in the U.K. and Switzerland.

Here too, XMRV was undetectable in plasma and PBMCs from any of the patients using PCR assays targeting XMRV gag or env. In addition, T-cell immune responses against XMRV gag were undetectable in PBMCs. "In our cohorts, XMRV was not enriched in patients with blood-borne or sexually transmitted infections from the United Kingdom and Western Europe," the researchers concluded.

In an accompanying editorial, Mary Kearney and Frank Maldarelli from the National Cancer Institute's HIV Drug Resistance Program noted that inconsistent XMRV findings could be attributable to factors including geographical variation, patient selection, and detection techniques. These 3 studies highlight the need for standardized assays, prospective epidemiological surveys, and sharing of samples among investigators. "Only when this is done in a rigorous fashion will it become clear what role XMRV or related viruses have in human disease," they wrote.

At a workshop on XMRV last week at Vall d'Hebron Hospital in Barcelona, Spain, investigators reported finding evidence of XMRV in 70% of tested chronic fatigue patients, according to a report from ABC Espana.

Researchers are exploring the hypothesis that CFS symptoms may be attributable to persistent immune system problems triggered by chronic infection with XMRV, herpes viruses, and possibly other infectious pathogens -- along similar lines as research linking non-AIDS conditions to excessive immune activation and ongoing inflammation in people with chronic HIV infection, even those on suppressive ART.

But skeptics suggest that XMRV and related retroviruses are not the underlying cause of conditions such as chronic fatigue, and their presence may simply reflect contamination of study samples with harmless, ubiquitous viral material.

Ila Singh from the University of Utah -- who published a key study last year linking XMRV to prostate cancer -- discussed this ongoing debate in a commentary in the November 3, 2010 online edition of the open access journal Viruses.

While a recently published study by Shyh-Ching Lo, Harvey Alter, and colleagues from the U.S. Food and Drug Administration (FDA) and National Institutes of Health (NIH) did not find XMRV itself in specimens from CFS patients, she noted, 87% of samples contained sequences from polytropic mouse endogenous retroviruses similar to XMRV.

"While each of these viruses, xenotropic, polytropic and modified-polytropic viruses (M-PMV), has been placed in distinct categories within the larger subgroup of murine leukemia viruses, it is important to note that they share considerable similarity with each other and utilize alleles of the same receptor for viral entry," she wrote. "Thus it is conceivable that PMV, M-PMV and XMRV may cause the same disease(s), if they cause disease at all."

In order to resolve the controversy, she suggested that future studies should include a large number of patients who have been diagnosed with CFS or myalgic encephalitis according to well-recognized clinical criteria -- such as the CDC's 1994 case definition -- rather than just vague clusters of symptoms. Control subjects should be healthy individuals from the same geographic area. Specimens from patients and controls should be collected, stored, and tested the same way by researchers blinded with regard to the sample source. Ideally, specimens should be examined using multiple tests, including at least one that has successfully detected XMRV previously.

Academic experts and CFS patient advocates gathered last week at a meeting in New York City convened by the Department of Health and Human Services -- led by renowned "virus hunter" Ian Lipkin -- to develop a plan for studying XMRV and its link to chronic fatigue, reminiscent of early collaboration among researchers, government officials, and HIV/AIDS activists.

Advocates are eager to pinpoint a definitive cause for CFS -- which affects upwards of 1 million people in the U.S., according to the CDC, about the same as the number living with HIV -- both to validate the experience of patients who have often been told the condition is "all in their head," and to open new avenues for developing effective treatments.

Investigator affiliation: Danielson study: Departments of Molecular Virology & Microbiology, Pathology, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX.

Henrich study: Divisions of Infectious Diseases and Allergy, Immunolog& Rheumatology, Brigham and Women's Hospital, Boston, MA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA; Ragon Institute of Massachusetts General Hospital, Boston, MA; Massachusetts Institute of Technology, Cambridge, MA; Harvard University, Cambridge, MA; Dana-Farber Cancer Institute, Boston, MA.

Barnes study: Nuffield Department of Clinical Medicine and James Martin 21st Century School, Peter Medawar Building for Pathogen Research, Oxford University, Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford, UK; Department of Gastroenterology, John Radcliffe Hospital NHS Trust, Oxford, UK; Division of Medicine, Wright Fleming Institute, Imperial College London, St. Mary's Hospital, London, UK; Institute of Microbiology, ETH Zurich, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital, University of Zurich, Zurich, Switzerland; Division of Infectious Diseases, University Hospital, Geneva, Switzerland.

Editorial commentary: HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Singh commentary: Department of Pathology, University of Utah, Salt Lake City, UT

References

BP Danielson, GE Ayala, and JT Kimata. Detection of xenotropic murine leukemia virus-related virus in normal and tumor tissue of patients from the southern United States with prostate cancer is dependent on specific polymerase chain reaction conditions. Journal of Infectious Diseases 202(10): 1470-1477 (Abstract). November 15, 2010.

TJ Henrich, JZ Li, D Felsenstein D, and others. Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions. Journal of Infectious Diseases 202(10): 1478-1481 (Abstract). November 15, 2010.

E Barnes, P Flanagan, A Brown, and others. Failure to detect xenotropic murine leukemia virus-related virus in blood of individuals at high risk of blood-borne viral infections. Journal of Infectious Diseases 202(10): 1482-1485 (Abstract). November 15, 2010.

M Kearney and F Maldarelli. Current status of xenotropic murine leukemia virus-related retrovirus in chronic fatigue syndrome and prostate cancer: reach for a scorecard, not a prescription pad (Editorial commentary). Journal of Infectious Diseases 202(10): 1463-1466. November 15, 2010.

I Singh. Detecting Retroviral Sequences in Chronic Fatigue Syndrome. Viruses. 2(11): 2404-2408 (Abstract). November 3, 2010.

Other Sources

Journal of Infectious Diseases. New Studies Examine Links Between XMRV and Human Disease. News advisory. October 12, 2010.

Un virus puede estar relacionado con el sindrome de la fatiga cronica. www.abc.es. November 2, 2010.

A Dockser Marcus. What's Next for X (as in XMRV)? Wall Street Journal Health Blog. November 4, 2010.