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Study Undermines XMRV Connection to Human Disease

XMRV particles, as visualized by transmission electron microscopy.Dr. Ila R. Singh, University of Utah

The retrovirus previously tied to prostate cancer and chronic fatigue syndrome (CFS) is unlikely to be responsible for either, according to new research. The virus appears to have arisen in the laboratory. The association with human disease was probably due to contamination of samples.

The xenotropic murine leukemia virus-related virus (XMRV) was first found in samples from a human prostate tumor in 2006. It was reported to be present in 6% to 27% of human prostate cancers. A study in 2009 also found XMRV in the blood of 67% of people with CFS. However, these results were challenged by several studies that failed to detect XMRV in samples from people with prostate cancer or CFS.

A research team led by Dr. Vinay Pathak of NIH’s National Cancer Institute (NCI) set out to investigate whether XMRV could have originated in the laboratory. When studying cancer, researchers often graft human tumors onto mice to create what are called xenografts. The scientists examined the process used to create the xenografts as well as the subsequent procedures that led to the identification of XMRV.

In the online edition of Science on June 2, 2011, the researchers reported that the initial prostate tumor xenografts didn’t contain XMRV, but that later tumors derived from them did. The virus appears to have infected the human tumor cells while they were in mice.

Closely related murine leukemia viruses are known to cause cancers and other diseases in mice. In the laboratory, these viruses can infect cells from other species, including humans. The team did a genetic search in the strains of mice previously used for xenografting the prostate tumor cells. They detected 2 previously undescribed viruses, which they dubbed PreXMRV-1 and PreXMRV-2. Genetic comparison of the PreXMRV-1 and PreXMRV-2 sequences revealed that each has a long stretch of DNA that’s nearly identical to XMRV.

The scientists postulate that genetic recombination between these 2 viruses generated XMRV while human prostate tumor cells were being grown in a mouse. The recombination — a common outcome when cells are infected by 2 or more viruses — likely occurred sometime between 1993 and 1996. The recombined virus then infected the human tumor cells.

Another report in the same issue of Science failed to find an association between XMRV and CFS, even in the same patients from the 2009 study. The research team found evidence of sequences from the 2 mouse viruses in commercial laboratory reagents. They concluded that the previous results likely stemmed from laboratory contamination.

“After the reports of XMRV in human prostate cancer, and later of XMRV in people with CFS, retrovirologists all over the world were excited to explore its role in human infection and disease,” Pathak says. “The results published today are not what we would have expected, but due to the time and resources dedicated to the understanding of this virus by researchers at NCI and NIH as well as others, scientists can now concentrate on identifying the real causes of these diseases.”

“Taken together, these results essentially close the door on XMRV as a cause of human disease,” says coauthor Dr. John Coffin, special advisor to the NCI director and a professor at Tufts University School of Medicine. Some evidence still suggests that these diseases may stem from viruses, but not from XMRV.