Hide and Seek

By Suzanne D. Vernon, PhD, Scientific Director of the CFIDS Association of America
November 2010

The November issue of the Journal of Infectious Diseases (JID) includes three papers and one editorial commentary on XMRV. The first of the papers, and the only one with positive findings, is from Danielson et al. from Baylor College of Medicine in Houston. It describes detection of XMRV in 32 of 144 (22%) men with prostate cancer.¹ These investigators extracted DNA from the surgically removed prostate tissue and detected the virus in both tumor and normal prostate tissue, indicating that XMRV infection may be present before cancer develops. They did not find an association with the RNaseL polymorphism, as has been suggested by other studies of XMRV in prostate cancer. However, they did find that XMRV detection depended on specific assay conditions, including the amount of DNA and the primers used to perform the PCR. There have now been a roughly equal number of publications that do and do not report evidence of XMRV in prostate cancer. Of those that have found XMRV, it is detected in about one-quarter of the cases. All the positive XMRV prostate cancer studies have been conducted in the U.S., although the negative studies come from groups in the U.S. and other countries.

The other two papers reported in this issue of JID looked for XMRV in blood samples. The paper by Henrich et al.² reports on a cohort of 293 patients seen at academic hospitals in Boston, including 32 CFS patients (meeting the Fukuda definition), 43 HIV patients, 26 hematopoietic stem-cell transplant or solid organ transplant patients, 97 rheumatoid arthritis (RA) patients, and 95 patients presenting for general medical care who were sex- and age-matched to the RA patients. The CFS patients included in the study had been sick for an average of 11 years; 69% were not able to continue working because of their CFS, and 75% had a flu-like onset of their symptoms. The nested PCR assay used primer sets shown to detect XMRV (by Lombardi et al. and Fischer et al.) and these investigators demonstrated that they could reliably detect 10 copies of XMRV DNA. A murine endogenous retrovirus was found in one RA sample, but they could not repeat the finding. No XMRV was detected in any of the 293 blood samples. The patient groups selected for this study are interesting because the investigators are testing the hypothesis that immune status (suppression or activation) may affect the prevalence of XMRV in different populations. Based on the outcome of this study, Henrich et al. conclude, “We did not identify an association between XMRV prevalence and immune status.”

The third paper looked for XMRV in individuals at high risk for blood-borne viral infections.³ Barnes and colleagues from Oxford University in the United Kingdom looked for XMRV in blood samples collected from 230 patients with human immunodeficiency virus type 1 (HIV-1) or hepatitis C (HCV) infection. They used PCR to detect viral DNA from blood cells and RNA from virus particles in the plasma. They also used an assay designed to test whether the immune cells recognize and remember XMRV. XMRV was undetectable in plasma or blood cells by PCR targeting XMRV gag or env genes. Immune cell responses to XMRV were also undetectable. In these United Kingdom and Western Europe cohorts, XMRV was not enriched in patients with blood-borne or sexually transmitted infections.

In the commentary on these three articles,⁴ Mary Kearney and Frank Maldarelli, both from the federal agency (National Cancer Institute) that worked with the Whittemore Peterson Institute to find XMRV in CFS patients, note that several factors may contribute to the varied detection of XMRV including geographic distribution, patient selection and assay and detection methods. They emphasize the need for standardization of methods, development of XMRV-positive control reference panels, sharing of reagents and prospective epidemiologic studies. Some of this is occurring through the blood safety study being coordinated by the National Heart, Lung and Blood Institute, but broader efforts are needed as well.

In addition, my training and experience suggests that studies of these agents in CFS cohorts should seek to replicate – as much as possible – the features of the CFS patients found to be positive for XMRV and MLV-related viruses in the studies published in Science and the Proceedings of the National Academy of Sciences. Possibilities for XMRV being opportunistic or a passenger virus seem to be narrowing based on the negative results in cohorts of patients with immune suppression, immune activation or blood-borne infections, so studying the specific characteristics of CFS patients testing positive is an important next step, without which XMRV might continue its game of hide and seek.

1. Danielson BP, Ayala GE, Kimata JT. 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. 2010 Nov 15;202(10):1470-7.
   
   
2. Henrich TJ, Li JZ, Felsenstein D, Kotton CN, Plenge RM, Pereyra F, Marty FM, Lin NH, Grazioso P, Crochiere DM, Eggers D, Kuritzkes DR, Tsibris AM. Xenotropic murine leukemia virus-related virus prevalence in patients with chronic fatigue syndrome or chronic immunomodulatory conditions. Journal of Infectious Diseases. 2010 Nov 15;202(10):1478-81.
   
   
3. Barnes E, Flanagan P, Brown A, Robinson N, Brown H, McClure M, Oxenius A, Collier J, Weber J, Günthard HF, Hirschel B, Fidler S, Phillips R, Frater J. 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. Nov 15;202(10):1482-5.
   
   
4. Kearney M, Maldarelli F. Current status of xenotropic murine leukemia virus-related retrovirus in chronic fatigue syndrome and prostate cancer: reach for a scorecard, not a prescription pad. Journal of Infectious Diseases. 2010 Nov 15;202(10):1463-6.

Suzanne D. Vernon, PhD, earned her doctorate in virology at the University of Wisconsin at Madison and worked in public health research on infectious diseases at the U.S. Centers for Disease Control and Prevention for 17 years before joining the CFIDS Association of America’s staff as scientific director in 2007. She has more than 70 peer-reviewed scientific publications on topics including human immunodeficiency virus, human papillomavirus, cervical cancer and chronic fatigue syndrome. Dr. Vernon has initiated and participated in numerous international and multidisciplinary research collaborations and she now leads the CFIDS Association’s research program. The CFIDS Association of America is the nation’s largest philanthropic supporters of CFS research.

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