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retrovirus

XMRV not detected in Dutch chronic fatigue patients

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dutch_cfs_xmrvThe suggestion that the retrovirus XMRV is the etiologic agent of chronic fatigue syndrome (CFS) arose from a study in which the virus was found in 68 of 101 US patients. The virus was not detected in two independent studies of 186 and 170 CFS patients in the United Kingdom. A new Dutch study has also failed to reveal XMRV sequences in 32 CFS patients.

The subjects of the Dutch study were part of a 298 member cohort. All patients fulfilled the Oxford criteria for CFS and reported debilitating fatigue for at least one year. Cryopreserved peripheral blood cells taken from 32 of these individuals between 1991-92 were used for preparation of DNA. This material was then subjected to polymerase chain reaction to amplify proviral XMRV DNA. The primer sets used were the same as those employed in the US study. Under the PCR conditions used, at least 10 copies of XMRV sequences could be detected per 100,000 peripheral blood mononuclear cells. All samples from CFS patients and from controls were negative for two different XMRV genes encoding integrase and gag proteins.

The authors consider a number of reasons why their results differ from those in the initial US CFS study. They rule out (1) technical differences; (2) The possibility that the long duration of CFS in the Dutch cohort may have led to negative results, because retroviruses integrate into the genome of the host; (3) cryopreservation; and (4) differences in cohorts. They suggest that XMRV might be involved in CFS outbreaks but not in sporadic CFS:

…the peripheral blood mononuclear cells [used in the US study] were derived from patients from the outbreak of chronic fatigue syndrome at Incline village at the northern border of Lake Tahoe, United States (1984-5). This outbreak has long been thought to have been caused by a viral infection and has been associated with a number of viruses, most notably Epstein-Barr virus and human herpes virus but firm evidence for a role of viruses in this particular outbreak has never been provided. It is possible that the study of Lombardi et al has unravelled the viral cause of the chronic fatigue syndrome outbreak, but it seems unlikely that their study demonstrates a viral association for sporadic chronic fatigue syndrome cases, such as those we tested, or represents the majority of patients. Studies of XMRV in sporadic chronic fatigue syndrome cases from the United States would be of great interest.

The authors do acknowledge the small sample size used in their study, which prevents them from statistically ruling out a role for XMRV in CFS. Nevertheless they conclude that “our data cast doubt on the claim that this virus is associated with chronic fatigue syndrome in the majority of patients.”

My office neighbor here at Columbia University Medical Center is Dr. Stephen Goff, an expert on retroviruses who has begun to investigate XMRV in his laboratory. He recently gave a plenary lecture on XMRV at the Conference on Retroviruses and Opportunistic Infections in San Francisco; you can hear some of his comments at medpage today. I poked my head in his office yesterday and asked him what he thought of the story so far. His answer: everyone needs to exchange samples, and they are not doing it. I couldn’t agree more.

Frank J M van Kuppeveld, Arjan S de Jong, Kjerstin H Lanke, Gerald W Verhaegh, Willem J G Melchers, Caroline M A Swanink, Gijs Bleijenberg, Mihai G Netea, Jochem M D Galama, & Jos W M van der Meer (2010). Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort British Medical Journal : 10.1136/bmj.c1018

XMRV not found in 170 additional UK chronic fatigue syndrome patients

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xmrv_neutralizationA new retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), first identified in tumor tissue of individuals with prostate cancer, was subsequently found in 68 of 101 US patients with chronic fatigue syndrome (CFS). XMRV was not detected in blood samples of 186 confirmed CFS patients in the United Kingdom. A second independent study in the UK (pdf) has also failed to reveal XMRV in CFS patients.

The subjects of this study were confirmed CFS patients from St George’s University of London, Barts and the London Hospital Trust, and Glasgow Caledonian University. A total of 170 serum samples from CFS patients and 395 controls were used. A polymerase chain reaction assay was devised that could detect as little as 16 copies of proviral XMRV DNA (viral DNA integrated into human chromosomal DNA). No XMRV sequences were detected in 142 CFS samples and 157 controls.

A second method was then used to search for evidence of XMRV: the patient serum samples were examined for the presence of antibodies that could block infection of cells with the virus. Cells were infected with XMRV in the presence of serum from CFS patients or control patients. Included were sera known to block XMRV infection to ensure that the assay functioned normally. None of 142 CFS samples contained antibodies that could block XMRV infection of cells. In contrast, 22 samples out of 157 controls (14%) were identified that contained neutralizing activity. One of 28 CFS serum samples from a separate cohort was found to contain XMRV neutralizing activity; none of the 12 control sera could block XMRV infection.

These results could be interpreted to mean that XMRV infection occurs in the general population, confirming the observations of the first US study. However, the sera from the second UK study also blocked the infectivity of viruses other than XMRV, including those containing envelope proteins from vesicular stomatitis virus. The authors believe that the neutralizing activity in the control sera is not specific for XMRV. These antibodies were probably induced by infection with another virus.

The results obtained with these samples do not provide evidence for an association of XMRV infection and CFS. This does not eliminate a role for XMRV in CFS. As the authors write:

The publication of these results has promoted much discussion and controversy amongst CFS researchers and patients alike, and has highlighted the need for additional investigations in this area. Following the findings reported here, it would seem a prudent next step for subsequent studies to compare samples and protocols between different laboratories around the world.

It’s time to put aside arguments over the competence of laboratories to carry out polymerase chain reaction and work towards understanding the role of XMRV in human disease. The three laboratories who have published their findings on XMRV in humans should exchange their samples to confirm the findings. Compelling answers will only come from far more extensive global studies of the prevalence of XMRV in CFS and control populations are clearly needed.

Harriet C T Groom, Virginie C Boucherit, Kerry Makinson, Edward Randal, Sarah Baptista, Suzanne Hagan, John W Gow, Frank M Mattes, Judith Breuer, Jonathan R Kerr, Jonathan P Stoye, & Kate N Bishop (2010). Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome Retrovirology : 10.1186/1742-4690-7-10

TWiV 66: Reverse transcription

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Hosts: Vincent Racaniello and Dickson Despommier

Vincent and Dickson continue virology 101 with a discussion of information flow from RNA to DNA, a process known as reverse transcription, which occurs in cells infected with retroviruses, hepatitis B virus, cauliflower mosaic virus, foamy viruses, and even in uninfected cells.

This episode is sponsored by Data Robotics Inc. To receive $50 off a Drobo or $100 off a Drobo S, visit drobostore.com and use the promotion code VINCENT.

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Weekly Science Picks
 Vincent Joint UN Programme on HIV/AIDS

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TWiV 65: Matt’s bats

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Hosts: Vincent Racaniello, Alan Dove, and Matthew Frieman

Vincent, Alan, and Matt discuss a project to study the RNA virome of Northeastern American bats, failure to detect XMRV in UK chronic fatigue syndrome patients, and DNA of bornavirus, an RNA virus, in mammalian genomes.

This episode is sponsored by Data Robotics Inc. To receive $50 off a Drobo or $100 off a Drobo S, visit drobostore.com and use the promotion code VINCENT.

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Matt 100 Incredible lectures from the world’s top scientists
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Vincent The Immortal Life of Henrietta Lacks by Rebecca Skloot

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XMRV not detected in German prostate cancer

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XMRVXenotropic murine leukemia virus-like virus (XMRV) was discovered in 2006 during a search for viral sequences in prostate cancer tissues. The results of a recent study revealed that the virus is present in 23% of prostate cancers from patients in the US. Understanding the role of XMRV in prostate cancers requires more extensive epidemiological studies, including the examination of tissues from patients in other countries. The prevalence of XMRV in prostate cancers from German subjects has now been assessed.

Prostate tissue samples were collected from 589 patients undergoing prostatectomy at the Universitätsmedizin Berlin. DNA was extracted from the biopsy material, and polymerase chain reaction (PCR) was used to detect the presence of XMRV. None of the samples were found to contain viral DNA. Furthermore, no antibodies to XMRV were detected in serum from 146 prostate cancer patients.

Two other studies have addressed the prevalence of XMRV in Germany and Ireland. In the German study, one of 105 samples from patients with prostate cancer was found to contain viral DNA. In the Irish study, no XMRV sequences were detected in 139 patient samples.

There are at least three ways to explain the results of the most recent German study. The trivial explanation is that the assay methods were not sufficiently sensitive to detect XMRV nucleic acid or antibodies. If I were working on the German samples, I would ask the authors of the American study to examine them for XMRV using their methods. Another possibility is that XMRV is geographically restricted. Alternatively, more than one gammaretrovirus might be associated with prostate cancer, which would not have been detected by the methods used by the German group.

Even after three years of research, the relationship between XMRV and prostate cancer is not understood. As Ila Singh has said, “We still don’t know that this virus causes cancer in people, but that is an important question we’re going to investigate.”

Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N, Denner J, Miller K, Kurth R, & Bannert N (2009). Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology, 6 (1) PMID: 19835577