Research: The tale of XMRV, new review, Journal of General Virology, 22 February 2012

February 23, 2012


From the Journal of General Virology, 22 February 2012.

The tale of xenotropic murine leukemia virus-related virus

Harriet C.T. Groom and Kate N. Bishop
MRC National Institute for Medical Research, London, UK

Abstract

In 2006, a new retrovirus was isolated from prostate cancer patient tissue. Named xenotropic murine leukemia virus-related virus (XMRV), this was potentially the third class of retrovirus to be pathogenic in humans.

XMRV made a more dramatic impact on the wider scientific community, and indeed the media, in 2009 when it was reported to be present in a remarkably high proportion of patients with chronic fatigue syndrome as well as a significant, albeit smaller, proportion of healthy controls.

The apparent strong link to disease and the fear of a previously unknown retrovirus circulating in the general population led to a surge in XMRV research.

Subsequent studies failed to find an association of XMRV with disease and, in most cases, failed to find the virus in human samples. In 2011, the case against XMRV and human disease strengthened, ending with several decisive publications revealing the origin of the virus and demonstrating contamination of samples.

In this review, we outline the passage of research on XMRV and its potential association with disease from its isolation to the present day, where we find ourselves at the end of a turbulent story.

Full paper HERE

4 thoughts on “Research: The tale of XMRV, new review, Journal of General Virology, 22 February 2012”

  1. Just finished reading this – it’s a fascinating tale. And clearly laid out for a change i.e. not full of minutiae that I can’t always fathom.

    This most recent paper wasn’t included in the review due to publication dates I suspect, but perhaps would have been featured (not that it alters the current thinking):

    Multiple Sources of Contamination in Samples from Patients Reported to Have XMRV Infection: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030889

  2. This review is a fascinating example of belief over evidence. Wrongly they ignore the diverse types of MLV type viruses that have been detected in patient samples, focusing on one unnatural strain called VP62. Neither Dr Mikovits or Ruscetti claimed to have found that xenotropic polytropic hybrid MLV-related virus. Their sequences being polytropic. A MLV type that is not covered by this review. This review is also limited to that one xenotropic polytropic variant, VP62 as I will explain.

    “xenotropic viruses (from the Greek xenos, meaning foreign) can infect a broad range of species with the exception of most commonly used laboratory mice” Groom and Bishop

    This from the paper has been found to be incorrect as you can see for this quote from Kozak 2010.

    ” The mouse xenotropic MLVs (X-MLVs) were originally defined by their inability to infect cells of their natural mouse hosts. It is now clear, however, that X-MLVs actually have the broadest host range of the MLVs. Nearly all nonrodent mammals are susceptible to X-MLVs, and all species of wild mice and several common strains of laboratory mice are X-MLV susceptible.” Kozak
    http://www.retrovirology.com/content/7/1/101

    The authors then state that the “ability of MLVs to cause pathology in other hosts, including humans, has not been documented.”

    This is potentially misleading if the reader is not familiar with the terminology, because Murine Leukemia Virus (MLV) like retroviruses (MLLVs) are found in several other species and do cause disease

    “MLLVs have spread among vertebrates in recent evolutionary time. The approximate time estimates to the last common MLLV progenitor are based on references given in the text, and on the phylogenetic analysis of Figure 1. Some gibbon apes in captivity have gibbon ape leukemia virus (GaLV). Koalas have recently been infected with koala retrovirus (KoRV). More distant relatives of the murine MLVs occur in pigs and cats. Porcine MLLV ERVs (PERVs) are MLLVs but the interspecies transmission routes are uncertain. Cats have several endogenous and exogenous MLLVs, including feline leukemia virus (FeLV)” (Blomberg, 2011)
    http://www.hindawi.com/journals/av/2011/341294/

    The authors next described how “Lombardi et al. (2009) generated great excitement, as the authors were able to detect XMRV in peripheral blood mononuclear cell (PBMC) DNA from 67% of their patient cohort compared with 4% of controls using nested PCR.”

    In reality the main labs never fully sequenced the isolates they had discovered in 67%, and their sequences were polytropic. Full sequencing was performed by Dr Silverman who had discovered polytropic xenotropic hybrid viruse(s) in prostate cancer patients. This was performed on only a small set of samples. Sadly instead of sequencing those isolates he sequenced the VP62 plasmid that was in his lab. A strain that is not found in nature. This was not discovered until recently and explains why labs who have designed assays for VP62 have not found that virus. This leaves the population still awaiting to be screened for the other viruses found in both prostate cancer and ME.

    The env region of MLV viruses determines their tropism, i.e. this region must be sequenced for the correct designation of a MLV virus. As the env region of the Lombardi viruses has not been sequenced, but the sequences so far are polyropic in their other regions, the Lombardi viruses cannot be said to be xenotropic.

    In 2010 the association was proven with the publication of a second ME paper that found polytropic sequences (Lo et al.).

    To be continued on another post…

  3. Potential for human infection and transmission

    MLV viruses have many mechanisms which they use to bypass the restriction factors that the authors mention, so it is not surprising that the viruses were found in blood. However, as MLV viruses are rarely found in blood it is not surprising that more studies have found it easier to detect these viruses in tissue rather than blood.

    Specifically the authors mention that APOBEC were able to restrict XMRV/VP62, “so it was unlikely that XMRV could maintain an efficient spreading infection in” PBMCs.

    However, the MuLV glycogag protects against APOBEC and APOBEC has no affect within mitotic cells. The majority of PBMCs are inactive (some 95%). Once an MLV gets inside one of these cells they cannot replicate or produce virions. MuLVs also integrate into B cells to evade APOBEC. The ability of APOBEC to restrict MLVs is therefore immaterial.

    “We report here a murine leukemia virus (MuLV) that utilizes its glycosylated Gag protein (gGag) to evade APOBEC3.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950561/

    Other human retrovirues have also found ways to block APOBEC even though they are affected by it.

    “These results suggest that MLV has evolved specific mechanisms to block the ability of Apobec proteins to mediate deaminase-dependent hypermutation.”
    “hA3G also caused significantly less hypermutation of MLV than of HIV DNA.”
    http://saturn.med.nyu.edu/research/mp/littmanlab/pubupdate/18032489.pdf

    “While many studies show that the APOBEC3 family of cytidine deaminases can inhibit human immunodeficiency virus type 1 (HIV-1) replication, the clinical significance of this host defense mechanism is unclear.”
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2259015/

    The authors also suggest that the evidence for sexual transmission of these viruses would not be complementary to the incidence of CFS, but they have applied this scenario to broad CFS criteria, unlike that used in Lombardi, and have not mentioned the evidence that MLVs are spread through saliva, though they do mention Fischer et al. (2010) who detected MLV-related viruses in the respiratory tract of people.

    Next they chose to cover animal research using VP62 inoculation. All of this research needs to be put into context. Animals do not exactly replicate the human body. They can only be used as a guide that may or may not be accurate to what would occurs in a human. What was notable in the animal research is that the virus rapidly cleared from the blood and settle in various tissues. This should alert scientists to the need for tissue research in ME patients, as it is also what occurs in mice. Some MLV viruses have never been detected in blood unless through artificial inoculation.

    “With regard to an association with CFS, pathological or not, the publication of several negative studies and the lack of replication in blood left the question open to serious doubt.”

    No replication study using the Lombardi methods has published and it is therefore wrong of the authors to use this term. Although the findings have been reproduced using other methods (Lo, 2010). This leaves no doubt that that there is no reason for doubting the results. This evidence is met with resistance from those unwilling to replicate.

    The authors do touch upon the Lo paper and how they detected polytropic env sequences.

    “However, the env sequences were more similar to those of modified polytropic MLVs than those of xenotropic viruses, a result that confounded rather than supported previous observations by Lombardi et al. (2009).”

    Sadly the authors fail to mention the polytropic gag sequences found in Lombardi and Lo. And that no env sequences were sequenced by the Dr Mikovits or Ruscetti for Lombardi et al. The only env region sequencing was performed by Dr Silverman, which as we now know, was in error.

    This statement is therefore false.

    “But why had Lo et al. (2010) found only polytropic and Lombardi et al. (2009) only xenotropic viruses? It seemed more likely that these could be artefacts.”

    The authors also make a plea for not using highly sensitive methods due to the risk of false positives due to contamination. This is the task of a scientists to find methods that do not react to a contaminant and which will detect viruses when present even in low numbers. This also fails to acknowledge the assays used in Uriman and Lombardi that are not prone to contamination. Use of appropriate contamination assays and procedures can also be used. It is sad to see scientists pulling away from asking if the viruses are there in low copy numbers that their clinically unvalidated assays cannot detect.

  4. The authors then move on to list several ways or origins for contamination, once again shutting their eyes to the assays that do not produce positive results if a contaminate was present.

    They suggest murine DNA, plasmids, commercial testing kits and accidental contamination taking place in other labs. The number of these accidental contamination’s should trouble the scientific community. As they are all evidence to support accidental spread of lab viruses. In relation to the positive studies, none of these were ever found to be responsible for the reported results.

    Finally the authors move on to the most popular speculation for contamination. As the viruses found in all these studies are not found in mice, commercial testing kits, and the samples from those studies do not contain plasmid contamination and the ME scientists never used mice or plasmids in their work, the next target was a cell line.

    The 22Rv1 cell line is claimed to be infected with XMRV, but only VP62, not VP35 or VP42 that were found in the first XMRV paper and are also called Xenotropic MLV-related viruses. The first question one would think to ask, is how can they be the origin of those viruses, or indeed polytropic viruses. Well 22Rv1 cannot be.

    It is therefore ridiculous to suggest this is a containment that could have created those viruses. Why also do all of these researchers who insist this is contamination despite the evidence always have 22Rv1 or VP62 present in their labs when testing human samples if this is a potential contaminate? The argument is not coherent and the risks of contamination in those studies is very likely.

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