Resumen CROI 2011: Dra. Suzanne Vernon

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[t]On the Origins of XMRV[/t]
Suzanne D. Vernon, PhD
Scientific Director
The CFIDS Association of America

I’ve spent the past few days watching some of the sessions webcast from the 18th Conference on Retroviruses and Opportunistic Infections (CROI), hoping for new insights into the role(s) that human gammaretroviruses, including XMRV and polytropic murine leukemia
virus-related viruses (MLVs) play in CFS and other diseases.

The session I listened to multiple times was titled, “XMRV: New Findings and Controversies.” It was held on March 2 and was available for viewing on March 3. Before introducing the presenters, session chairman Jonathan Stoye gave a brief overview of the original publication that found XMRV in prostate cancer tissue. He reported that subsequent studies of prostate cancer were discrepant on finding XMRV, but most found XMRV and the virus has been shown to be integrated in the cancer tumors. Stoye indicated that this integration has recently been disputed, referring to a paper published in Retrovirology on Feb. 25, 2011 by Garson et al. He wrapped up his introduction by saying that the original findings of XMRV and CFS published by Lombardi et al have not been replicated in other studies and therefore it seems unlikely that XMRV is associated with CFS.
Stoye stated that he does not consider the MLV study by Lo et al to confirm the Lombardi study. He outlined the important outstanding questions as: 1) Virus distribution – which would require reproducible detection methods in order to study disease association; and 2) the
origin of XMRV. I will summarize the eight two-minute presentations from this session and as you will see, there are many more than two important outstanding issues to consider. The abstracts for these talks and other XMRV-related research from the CROI website provide
additional details.

KyeongEun Lee, Marta Curriu, Jorge Carrillo and Mary Kearney presented on methods of detecting the virus. (A detailed, but fairly accessible, article about various testing methods was published recently in BioTechniques.) Lee described the DERSE cell line and showed that it
could support replication of XMRV but that plasma obtained from prostate cancer patients tested negative for XMRV. Curriu described how tonsil tissue could be infected with XMRV and might provide a suitable model for studying XMRV latency, or how viruses remain “dormant” in certain types of cells. Carrillo showed that some Epstein-Barr virus (EBV)-transformed B cell lines derived from CFS, HIV, prostate cancer and healthy people harbored XMRV sequences. The abstract of his presentation indicated that XMRV was found in 4 CFS, 1 HIV and 2 healthy controls cell lines. Kearney described a technique that could detect of single copy of XMRV or MLV in the same assay (X-SCA) and an approach for sequencing single XMRV genomes. Using
X-SCA, Kearney was not able to detect XMRV in 26 CFS samples from four patients who were reported to be XMRV-positive in the Lombardi paper, nor in 134 prostate cancer patients of unknown XMRV status. However, she was able to detect XMRV DNA in the blood of two macaques consistently up to 80 days post-inoculation.

Timothy Henrich and William Switzer looked for XMRV and MLVs in CFS samples and were not able to find evidence of infection with these viruses. Henrich’s team tested three patients who had previously received positive XMRV or MLV results from another laboratory, although neither his talk nor the abstract indicate which lab(s) did the tests. Switzer’s data was based on a second CDC study of XMRV/MLVs in CFS, the results of which were published in Retrovirology on Feb. 22, 2011.

Stephane Hue and Oya Cingoz examined the origins of XMRV. Hue conducted a phylogenetic analysis (like a family tree) of the XMRV sequences from CFS samples, prostate cancer samples and the 22Rv1 cell line. He showed that the XMRV sequences clumped together in one
cluster and this cluster was separated from other MLVs that were in other closely related but distinct “clumps.” He showed significant differences between the 22Rv1 cell line and patient samples and concluded that XMRV was a result of contamination. In an attempt to determine where XMRV came from, Cingoz examined some of the nude mice passages of a prostate cancer tumor for XMRV sequences. She found two endogenous MLVs that could mix and match to make a virus that would be identical to XMRV. (This information was presented in more detail by Vinay Pathak in a session held the previous day.)

These very brief presentations were followed by 30 minutes of discussion. People asked good questions and provided thoughtful comments. Other important questions were raised about topics not addressed, including the anecdotal reports (from the internet) about antiretroviral therapy. John Coffin repeated his caution from last fall’s XMRV Workshop that a controlled clinical trial of antiretroviral therapy should be conducted because of the difficulty of interpreting anecdotal reports. Interesting points were raised about the lower rates of prostate cancer seen in HIV populations and sporadic XMRV positives in people who work with XMRV in the laboratory. CDC’s Switzer said that his lab would be testing archived samples collected from lab workers. Mike Busch, who is involved with the XMRV blood safety study using CFS samples, expressed concern about the intermittent positive results of some lab workers who handle the virus.

Kathy Jones, who moderated the session with Stoye, noted that XMRV was a replicating virus that behaved differently from other gammaretroviruses and stated that it could productively infect primary cells. Stoye agreed that the behavior of XMRV was interesting and said that it was likely the biology of XMRV would continue to be studied, but he predicted that there would be less and less interest in studying the association of XMRV with disease.

I agree that standardized, validated assays must be a priority for the field. The discussion about ways in which XMRV behaves differently than other gammaretroviruses and its ability to establish productive infection highlight the need for continued disease association research. The list of important outstanding issues grew longer, rather than shorter, after hearing these presentations. Even though the evidence indicates XMRV evolved in a lab, that doesn’t imply that its current existence is benign.

Darwin did not have the advantage of understanding how viruses contribute to the evolution and adaptation of species. We now know that viruses are some of the most rapidly evolving “species” on the planet. This seems to be a prime opportunity for scientists to put
fractious politics aside, consider all the facts and keep an open mind before concluding that there are no diseases associated with XMRV.

March 4, 2011

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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Gracias Eli!

Buen resumen y cortito.

Con lo que se sabe están apunto de publicar tanto Cheney como De Meirler, todo esto va a cambiar MUCHO... ¡Es que dista tanto lo que espero salga a la luz de lo que intentan cada vez con más énfasis concluir...!

Como en todo, el tiempo dirá, y espero que a nuestro favor.

Por cierto, y aunque no cuente, pues quiero cambios más plausibles, y aún es muy pronto, yo sigo mejorando, tratando el XMRV, u otras infecciones con GcMAF. Y desde luego NO soy el único... Así que, que no me digan que estos virus son benignos, pues no puedo creerlo.

Sergio