Case Closed

On the heels of study results that de-linked CFS and XMRV comes a report from an equally robust group of researchers that severs the link between XMRV and prostate cancer.

Scientists at University of California, San Francisco (UCSF), Cleveland Clinic and Abbott collaborated using cutting-edge laboratory technology to trace the series of events that resulted in positive tests for XMRV in tissue samples obtained from men with prostate cancer, as reported in 2006.[1] Their paper published today in PLoS ONE [2] closes the case on this investigation and any remaining questions about the role of XMRV in prostate cancer.

The team was able to identify cells called LNCaP cells that were used in the same laboratory as samples from the prostate tumors under study in the early 2000s. These LNCaP cells were contaminated with XMRV, a virus shown by Paprotka et al to have been created by accident in a laboratory experiment by scientists working with mice and prostate cancer tumors to make an experimental cell line called 22Rv1.[3]

Robert-Silverman1The authors of the PLoS ONE paper include key members of the team that first discovered XMRV in prostate cancer tumor cells. The Cleveland Clinic’s Robert Silverman, Ph.D., is among them. Dr. Silverman was also a member of the group that identified XMRV in CFS samples in the original report from Lombardi et al.[4] Dr. Silverman states in a press release issued today by UCSF,

“It’s been known for over a year that XMRV was the result of lab contamination. I couldn’t rest until we figured out how it happened. It felt like the right thing to do was to collaborate with Dr. [Charles] Chiu and the others to get the answers. I’m gratified we finally got to the bottom of the story.”

Dr. John Hackett of Abbott, another of the study authors who has participated in some of the CFS-related XMRV studies, focused on the new technologies that have improved scientists’ abilities to understand the true nature of discoveries of potential pathogens. “If these scientific tools were available when XMRV was first discovered, contamination would likely have been identified far sooner.”

The PLoS ONE paper recognizes that XMRV is a real virus with “unique biology and as-yet undefined pathogenic potential.” But the authors make it clear that their findings “do not support any association between XMRV infection and prostate cancer, and by extension indicate that XMRV has never replicated outside of the laboratory setting.” Although other investigator teams were able to experimentally infect both mice and two species of non-human primates with XMRV by infusing large doses of the virus [5][6], it was reported at the 1st International Workshop on XMRV that no signs or symptoms of disease were observed in the infected animals. It is unknown whether XMRV could infect humans and those experiments would be ethically challenging to conduct. Several groups have reported that there are natural restriction factors that would be likely to interrupt the virus’ life cycle in a human host.[7]

Charles-ChiuThe topic of prostate cancer’s link to XMRV has been questioned for months, especially following retractions of the two original reports linking XMRV, then polytropic murine leukemia virus-like viruses, to CFS. The question was asked this morning at the Center for Infection and Immunity’s press conference about the multicenter study that found no XMRV or pMLVs in samples from 147 CFS cases and 146 matched healthy controls. This paper settles that question. As its senior author, Dr. Chiu of UCSF stated, “This is basically the nature of science — fallible and not necessarily error-free, yet ultimately self-correcting.” We applaud this team’s efforts to search out an answer and correct the record. It’s a remarkable piece of scientific detective work to have traced samples from two decades ago and determined how they reached now-erroneous conclusions. And it’s a courageous act to right the record in a forthright way.

Shortly after this paper was published, the editors of PLoS Pathogens retracted the original paper by Urisman et al., stating “…it is clear that XMRV found in this study is laboratory-derived and there is no association of XMRV with prostate cancer. As a result the paper was retracted from PLOS Pathogens on September 18th, 2012.” This move, made without first notifying the authors, provoked debate about when to retract and when to amend studies later proven incorrect. We’ve provided some of the links to articles on that topic below.

If history plays out with this prostate cancer-focused study as it has for other XMRV-related research, it will receive far less attention from the press than today’s CFS-related study. We’ve updated this page with links to media coverage, below.

References

1. Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, et al. (2006) Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASE L variant. PLoS Pathog 2: e25.

2. Lee D, Das Gupta J, Gaughan C, Steffen I, Tang N, et al. (2012) In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer. PLoS ONE 7(9): e44954. doi:10.1371/journal.pone.0044954

3. Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung HJ, et al. (2011) Recombinant origin of the retrovirus XMRV. Science 333: 97–101.

4. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, et al. (2009) Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 326: 585–589.

5. Onlamoon N, Das Gupta J, Sharma P, Rogers K, Suppiah S, et al. (2011) Infection, viral dissemination, and antibody responses of rhesus macaques exposed to the human gammaretrovirus XMRV. J Virol 85: 4547–4557.

6. Sakuma T, Tonne JM, Squillace KA, Ohmine S, Thatava T, Peng KW, Barry MA, Ikeda Y. (2011) Early events in retrovirus XMRV infection of the wild-derived mouse Mus pahari. J Virol. 2011 February; 85(3): 1205–1213. Published online 2010 November 17. doi: 10.1128/JVI.00886-10

7. Chaipan D, Dilley KA, Paprotka T, Delviks-Frankberry KA, Venkatachari NJ, Hu W-S, Pathak VK. (2011) Severe restriction of xenotropic murine leukemia virus-related virus replication and spread in cultured human peripheral blood mononuclear cells. J Virol. 2011 May; 85(10): 4888–4897. doi: 10.1128/JVI.00046-11Resources

PLoS ONE paper from Lee et al.: http://bit.ly/T0AERW

Press release from UCSF: http://bit.ly/V9Gfmh

Media Coverage

K. Kimberly McCleary served as the Association’s chief staff executive from 1991-2013. She has participated in dozens of research and patient conferences on CFS and related conditions. She served on the Department of Health and Human Services CFS Coordinating Committee from 1996 until 2001, has testified before Congress numerous times, and has given scores of media interviews about CFS.

September 18, 2012