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Minutes, 7 May 2010 meeting of National Expert Panel on New and Emerging Infections

Discussion in 'XMRV Research and Replication Studies' started by Dx Revision Watch, Sep 16, 2010.

  1. Dx Revision Watch

    Dx Revision Watch Dx Revision Watch no longer posts

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    Dr Charles Shepherd (Trustee and Honorary Medical Advisor to the ME Association) published these minutes via Co-Cure on 16 September.


    MAY BE REPOSTED

    Minutes of the 7 May 2010 meeting of that [sic] National Expert Panel on New and Emerging Infections

    Summary of discussion by subgroup on XMRV:

    http://www.dh.gov.uk/prod_consum_dh.../@dh/@ab/documents/digitalasset/dh_118427.pdf

    ------------------------------

    I have converted the text from the PDF

    Page 1

    Final 14/7/2010, corrected 04/08/2010


    National Expert Panel on New and Emerging Infections Meeting of Subgroup on Xenotropic Murine Leukaemia Virus-Related Virus (XMRV)

    Summary of Discussion

    7 May 2010, Skipton House, Department of Health

    Present

    Subgroup members

    Professor Andy Hall (Chair) National Expert Panel on New and Emerging Infections (NEPNEI)
    Dr David Brown Health Protection Agency Virus Reference Department
    Professor Myra McClure Imperial College London
    Professor Tim Peto University of Oxford
    Dr Falko Steinbach Veterinary Laboratories Agency
    Dr Jonathan Stoye National Institute for Medical Research
    Professor Richard Tedder Health Protection Agency Virus Reference Department
    Professor Jonathan Weber Imperial College London

    Agency Assessor
    Mrs Maggie Tomlinson Department of Health

    Observers
    Ms Julia Granerod Secretariat to the Advisory Committee on Dangerous Pathogens
    Ms Charlie Mirrielees Department of Health

    Secretariat
    Miss Georgia Ladbury Health Protection Agency
    Dr Dilys Morgan Health Protection Agency

    Apologies
    Professor Will Irving Member of the National Expert Panel on New and Emerging Infections
    Dr Philip Minor National Institute for Biological Standards and Control
    Professor Greg Towers University College London


    Key messages

    The consensus conclusions were:

    XMRV can infect humans but there is currently no evidence that it causes human disease

    Development of a robust diagnostic tool to accurately detect infection is a priority
    for further investigation of this infection

    Page 2

    Further work is required to investigate tissue tropism and pathogenicity,
    epidemiology of infection and whether this infection is of any public health significance

    On the evidence before the Group, no public health action is required at this time

    XMRV infection

    The papers listed at Annex A to these minutes were provided to the Members of the
    Group prior to the meeting. Members reviewed the scientific evidence and summarised
    it as follows:

    Xenotropic murine leukaemia virus-related virus (XMRV) was first detected in 2006 in
    human prostate cancer tissue. XMRV is most similar to the murine leukaemia viruses
    (MuLVs). The gammaretrovirus genus of Retroviridae are simple viruses known to
    infect a diverse range of mammalian species, causing leukaemia and other diseases in
    their respective hosts. XMRV is the first gammaretrovirus known to infect humans.
    Infection with the virus may not necessarily cause human disease, and evidence to
    demonstrate disease association or causality is lacking. There are conflicting published
    data. Various studies have linked the virus to prostate cancer and more recently to
    chronic fatigue syndrome (CFS), but other studies have been unable to reproduce those
    findings. There are also studies that have demonstrated evidence of lack of disease
    association. Routes of transmission for infection remain unknown.

    The known oncogenic properties of mammalian gammaretroviruses in their animal
    hosts makes an assessment of the public health significance of the finding of XMRV in
    humans important.

    It is not yet known whether XMRV is a recently evolved virus, or whether it has been
    circulating for some time. The available evidence showing the virus has the capacity to
    integrate into human genomic DNA and the heterogeneity in the sequence data,
    together with viral isolation and demonstration of viral antigen expression, strongly
    indicates that XMRV is an exogenous human infection.

    The pattern of viral distribution in human tissues following infection is unclear. Work
    done so far suggests that the tissue tropism of XMRV is very different to the T cell
    tropism seen with other human retroviruses such as HIV and HTLV.

    Current detection methods

    There is as yet no gold standard nor agreed standardised diagnostic tests for the
    detection of XMRV infection. The variability in methods used to detect XMRV by
    various research groups may partially explain the different findings of the research
    groups.

    Diagnostic detection methods used to date include: PCR to detect viral genome in
    tissue or peripheral blood mononuclear cells (PBMCs); RT-PCR and culture to
    demonstrate viraemia in plasma; immunofluorescence to demonstrate viral antigen; and
    serology to demonstrate a host response to infection. Each of these methods has
    potential shortcomings and may result in false negative and false positive reactions.

    Page 3

    The sensitivity and specificity of the various tests used to date are unknown and there is
    a worrying lack of concordant positive reactions. When XMRV has been detected in
    prostate cancer tissue, it has not proved possible to detect the virus in PBMCs or
    serologically under any conditions. Multiple assays may therefore be needed to
    determine XMRV infection definitively, especially if using PCR based technology.
    XMRV shares DNA sequence homology with endogenous retroviruses existing in the
    mouse genome. This can lead to false positive results in laboratories that also work on
    mice. The possibility of contamination is compounded by the fact that many
    laboratories use MuLV plasmids as vectors for several areas of work. This could
    potentially lead to false positive tests for XMRV, owing to murine DNA being detected
    rather than human DNA. This issue makes sample sharing between laboratories for
    corroboration of findings difficult (as contaminated tissue would always generate false
    positives). Members considered it essential that any future investigative work in the UK
    should be done using samples that have been obtained within the UK under strict
    sampling protocols, preferably using fresh tissue samples.

    XMRV and prostate cancer

    Prostatic cancer tissue is where XMRV has frequently been found. It is also where it has
    been looked for, and there is no evidence so far of XMRV isolation from other tissue.

    Members considered the current epidemiological data unconvincing, and insufficient to
    indicate any disease relationship or disease causality due to the presence of XMRV in
    prostate tissue. Members were of the view that there was no evidence of any
    geographical differences in XMRV distribution.

    Members agreed, however, that though there is no evidence that XMRV is associated
    with prostate cancer, the fact that gammaretroviruses are known to have oncogenic
    properties in a variety of mammalian species raises the index of suspicion. With this in
    mind, Members considered what further studies could be carried out to investigate
    XMRV in relation to prostate cancer tissue. It was noted that control groups have been
    small in the published studies conducted so far. More studies are needed in which
    there are adequate controls that are representative of the general population. It was
    agreed that challenges exist in identifying suitable controls for prostate cancer studies,
    as in older age groups intraepithelial neoplasia is common, making it difficult to
    distinguish cases from controls. Members considered that there would be value in
    undertaking studies to investigate the presence of XMRV in seminal fluid and vaginal
    biopsies, to both assess potential sexual transmission and potentially to aid detection.
    XMRV and chronic fatigue syndrome (CFS)

    A potential association between CFS and XMRV infection was first made by Lombardi
    et al in October 2009, a research group from the Whittemore Peterson Institute in the
    USA. This Institute was set up to specifically research the pathophysiology of diseases
    such as CFS. However, three studies have been published in which the researchers
    failed to replicate Lombardi’s findings. Members considered that these 'negative'
    studies were valid and, together with their knowledge of the results of two further
    studies awaiting publication (CDC study – Switzer et al 2010, Retrovirology in press;
    Boston study – Huber et al, in preparation) that failed to demonstrate any association of
    XMRV with CFS, provided good evidence of a lack of association with CFS.

    Page 4

    Though retroviruses are known to induce oncogenesis, XMRV is known to behave quite
    differently and distinctly from other retroviruses, and a biological mechanism by which
    XMRV could induce syndromes such as CFS has not been proposed.

    Implications for public health

    A number of studies have identified the virus to be present in the general population. So
    far it is not known whether there is any association between XMRV presence and
    disease, or what, if any, public health implications there could be.

    In November 2009 a risk assessment for XMRV was carried out by the Standing
    Advisory Committee for Transfusion Transmitted Infection (SACTTI), one of the
    committees of the Joint United Kingdom Blood Transfusion Services and National
    Institute of Biological Standards and Control Professional Advisory Committee (JPAC).

    The risk assessment was considered by JPAC at its meeting in November 2009, and
    JPAC concluded that there was insufficient evidence to recommend that a history of
    past CFS should be actively sought from potential blood donors, in order to exclude
    them from blood donation. Current blood service guidance ensures that potential blood
    donors who self-report as being chronically unwell are excluded from donation and this
    includes those suffering from CFS. These exclusions are for the benefit of donors since
    the UK Blood Services do not wish to risk there being any association between blood
    donation and a subsequent coincidental exacerbation of donors' illness. Current UK
    Blood Service guidelines also exclude as donors those with a current or past history of
    malignancy, and this includes prostate cancer.

    Members of the Subgroup agreed that in the absence of evidence that XMRV is
    associated with prostate cancer, and in view of the evidence of a lack of association
    with CFS, no public health action is indicated currently. However, Members agreed that
    further work is needed to address the gaps in knowledge about XMRV biology,
    pathology and epidemiology.

    Knowledge gaps and priority work required

    The priority is for the development of a validated reproducible method of detection of
    XMRV. This would facilitate definitive epidemiological studies to investigate the
    presence of the virus in the general population and in relation to prostate cancer.

    A serological assay would be the most useful detection tool to screen populations for
    infection. Members were informed that there is already collaborative work ongoing with
    the HPA to develop such an assay but that this work is limited by resources, and there
    has been no specific funding earmarked for this activity.

    The epidemiology of infection needs to be studied in order to deduce routes of
    transmission. The prevalence of infection in the general population is unknown and
    larger analytical studies are needed to investigate possible disease associations.

    Further work is needed to investigate the distribution of the virus in tissues, and to
    establish whether XMRV is a newly evolved virus. Members recognised the need for,
    and constraints associated with, obtaining ethical approval for the appropriate studies.

    NEPNEI secretariat
    May 2010, corrected 04/08/10


    Page 5

    Annex A – Papers supplied to members

    Abstract from Klein et al, Genitourinary Cancers Symposium 2010. Available at:
    http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&con fID=73&abstractID=30543

    Arnold RS, Makarova NV, Osunkoya AO, Suppiah S, Scott TA et al. XMRV
    infection in patients with prostate cancer: novel serologic assay and correlation
    with PCR and FISH.
    Urology 2010 Apr;75(4):755-61.

    D'Arcy F, R. Foley, A. Perry, L. Marignol, M. Lawler, E. Gaffney, R.G.W. Watson,
    J.M. Fitzpatrick, T.H. Lynch. No evidence of XMRV in Irish prostate cancer patients
    with the R462Q mutation.
    European Urology Supplements, 7 (3): 271, March 2008.

    Dong B, Kim S, Hong S, Das Gupta J, Malathi K, Klein EA, Ganem D, Derisi JL,
    Chow SA, Silverman RH. An infectious retrovirus susceptible to an IFN antiviral
    pathway from human prostate tumors.
    Proc Natl Acad Sci U S A. 2007 Jan
    30;104(5):1655-60.

    Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A.
    Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS
    One. 2010 Jan 6;5(1):e8519.

    Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H, Aepfelbacher M, Schlomm
    T. Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. J
    Clin Virol. 2008 Nov;43(3):277-83.

    Furuta RA, Miyazawa T, Sugiyama T, Kimura T, Hirayama F, Tani Y, Shibata H.
    The Prevalence of Xenotropic Murine Leukemia Virus-Related Virus in Healthy
    Blood Donors in Japan. In Abstracts of papers presented at the 2009 meeting on
    Retroviruses, May 18 - May 23, 2009 Cold Spring Harbour Laboratory.
    pp. 100;
    2009:100.

    Groom HC, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, Gow JW,
    Mattes FM, Breuer J, Kerr JR, Stoye JP, Bishop KN. Absence of xenotropic murine
    leukaemia virus-related virus in UK patients with chronic fatigue syndrome.

    Retrovirology. 2010 Feb 15;7:10.

    Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N, Denner J, Miller K,
    Kurth R, Bannert N. Lack of evidence for xenotropic murine leukemia virus-related
    virus (XMRV) in German prostate cancer patients.Retrovirology.
    2009 Oct
    16;6(1):92

    Knouf EC, Metzger MJ, Mitchell PS, Arroyo JD, Chevillet JR, Tewari M, Miller AD.
    Multiple integrated copies and high-level production of the human retrovirus XMRV
    (xenotropic murine leukemia virus-related virus) from 22Rv1 prostate carcinoma
    cells. J Virol.
    2009 Jul;83(14):7353-6.

    Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL,
    Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH,

    Page 6

    Mikovits JA. Detection of an Infectious Retrovirus, XMRV, in Blood Cells of
    Patients with Chronic Fatigue Syndrome. Science.
    2009 Oct 23;326(5952):585-9.

    Paprotka T, Venkatachari NJ, Chaipan C, Burdick R et al. Inhibition of Xenotropic
    Murine Leukemia Virus-Related Virus by APOBEC3 proteins and antiviral drugs.
    J
    Virol 2010 Mar 24. [Epub ahead of print]

    Rokman A, Ikonen T, Seppaa EH, Nupponen N, Autio V, Mononem N, et al.
    Germline alterations of the RNASE L gene, a candidate HPC1 gene at 1q25, in
    patients and families with prostate cancer.
    Am J Hum Genet 2002; 70(5): 1299-
    304.

    Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR. XMRV is present in
    malignant prostatic epithelium and is associated with prostate cancer, especially
    high-grade tumors. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16351-6.
    Selected abstracts from Conference on Retroviruses and Opportunistic Infections
    2010 (Sharma et al, Qiu et al, Bhosle et al, Dong et al)
    available at:
    http://www.retroconference.org/2010/display.asp?page=493.

    Singh IR, Gorzynski JE, Drobysheva D, Bassit L, Schinazi RF. Raltegravir is a
    potent inhibitor of XMRV, a virus implicated in prostate cancer and Chronic Fatigue
    Syndrome. PLoS One 2010 Apr 1;5(4):e9948.

    Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K,
    Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL. Identification of a
    novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q
    RNASE L variant.
    PLoS Pathog. 2006 Mar;2(3):e25.

    van Kuppeveld FJ, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJ, Swanink
    CM, Bleijenberg G, Netea MG, Galama JM, van der Meer JW. 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.
    BMJ. 2010 Feb 25;340:c1018.

    [Ends]
     
  2. Dx Revision Watch

    Dx Revision Watch Dx Revision Watch no longer posts

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    I am putting a text version of these Minutes out on Co-Cure, today.

    ETA: Nico Vanden Eynde, Co-Cure Moderator, has rejected a copy of the full text on Co-Cure.

    There is more likelihood of a document being read if it is presented in text format; it also makes it easier to quote from, so I am not best pleased that a Co-Cure mod has not accepted a text version of this important document for international circulation.
     
  3. Daffodil

    Daffodil Senior Member

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    "...a biological mechanism by which XMRV could induce syndromes such as CFS has not been proposed."

    that is not true..the WPI proposed mechanisms by which XMRV might cause inflammation and CFS.
     
  4. Dx Revision Watch

    Dx Revision Watch Dx Revision Watch no longer posts

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  5. Angela Kennedy

    Angela Kennedy

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    Conflict of interests of sub group members not disclosed then?
     
  6. Sasha

    Sasha Fine, thank you

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    I don't get any real sense of urgency from this but this was before the Alter paper and the XMRV workshop in Bethesda. I can't see anywhere where they talk about how often they're going to review the situation, though.

    Doesn't look to me as though we can rely on the UK Dept of Health to be a major player at this stage. Meanwhile, back in the US...
     

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