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Emerging Infectious Disease Agents/XMRV/Transfusions

Discussion in 'XMRV Research and Replication Studies' started by Hysterical Woman, Feb 4, 2010.

  1. Hysterical Woman

    Hysterical Woman Senior Member

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    East Coast
    Not sure if this has already been posted somewhere? It is from XMRV Global Action via Facebook.

    Xenotropic murine leukemia virus-related
    virus (XMRV)
    Disease Agent:
    • Xenotropic murine leukemia virus-related virus (XMRV)

    Disease Agent Characteristics:

    • Family: Retroviridae; Subfamily: Orthoretrovirinae; Genus:
    Gammaretrovirus; Species: Xenotropic murine leukemia
    virus-related virus (XMRV)
    • Virion morphology and size: Virions have a complex construction
    and consist of an envelope, a nucleocapsid, and a
    nucleoid. Virions are spherical to pleomorphic measuring
    80-100 nm in diameter. Virions have a buoyant density in
    sucrose of 1.15-1.17 g cm
    -3.
    • Nucleic acid: The genome is a dimer of linear, positivesense,
    single-stranded RNA, 8300 nucleotides long.
    • Physicochemical properties: As enveloped retroviruses, the
    virions should be susceptible to heat, detergents and many
    disinfectants such as 1% sodium hypochlorite, 2% glutaraldehyde,
    formaldehyde and ethanol.

    Disease Name:

    • Evidence of association, but not causation, has been
    reported for XMRV infection with the following conditions:
    Prostate cancer
    Chronic Fatigue Syndrome (CFS)

    Priority Level:

    • Scientific/Epidemiologic evidence regarding blood safety:
    Theoretical; although pathogenic retroviruses (i.e., HIV and
    HTLV) are clearly transfusion transmitted, such transmission
    of XMRV has been neither demonstrated nor alleged.
    There are no data suggesting an association of prostate
    cancer or CFS with transfusion.
    • Public perception and/or regulatory concern regarding
    blood safety: Moderate based on the characteristics of other
    retroviruses and the early stage of investigations of the clinical
    associations of human infection with this agent. Concern
    has been publicly expressed regarding transfusion transmission
    of XMRV following publication of data associating it
    with CFS.
    • Public concern regarding disease agent: Low at least partly
    based on lack of familiarity with a virus only very recently
    associated with any prevalent human disease; however, may
    be higher in groups with diseases associated with XMRV.

    Background:

    • A diverse range of mammalian species is susceptible to infection
    by gammaretroviruses. These are simple retroviruses
    whose genomes encode only
    gag, pro, pol, and env genes.
    They include murine leukemia virus, feline leukemia virus,
    koala retrovirus, and gibbon ape leukemia virus that cause
    leukemia and other syndromes in their host species.
    • Evidence of human infection with gammaretroviruses was
    lacking until 2006 when genomes of a previously undescribed
    gammaretrovirus, XMRV, were detected in a cohort
    of US men with a familial aggregation of an aggressive form
    of prostate cancer. The hypothesis was that these men, who
    harbored a homozygous mutation of the antiviral enzyme
    RNase L, were unusually susceptible to the oncogenic potential
    of the virus. However, in a subsequent study, XMRV DNA
    or proteins were found in 6 and 23%, respectively, of malignant
    prostates irrespective of the RNase polymorphism.
    Studies in a German cohort did not detect XMRV infection
    in nearly 600 prostate cancer samples.
    • In 2009, a statistical association of XMRV infection with CFS
    was reported. Peripheral blood mononuclear cells (PBMC)
    from 67% of stringently defined CFS patients contained the
    proviral DNA of XMRV compared to 3.7% of healthy controls.
    These patients did not have the RNase L polymorphism
    mentioned above. Secondary infections in tissue
    culture could be established from PBMCs, B and T cells and
    plasma of patients. The study concluded, “(T)hese findings
    raise the possibility that XMRV may be a contributing factor
    in the pathogenesis of CFS.”
    • Whether the association of XMRV infection with these syndromes
    is causal or is confounded by factors like geographic
    variability of the prevalence of the virus or the presence of
    unusual susceptibility to viral infection in the clinical cohorts
    studied is unknown. Published studies lack a complete
    description about selection of the CFS patient and control
    cohorts.

    Common Human Exposure Routes:

    • Unknown

    Likelihood of Secondary Transmission:

    • Unknown

    At-Risk Populations:

    • Unknown

    Vector and Reservoir Involved:

    • Unknown

    Blood Phase:

    • A perspective accompanying the original CFS study concluded
    “(G)iven that infectious virus is present in
    plasma and in blood cells, blood-borne transmission is a
    possibility.”

    Survival/Persistence in Blood Products:

    • Unknown

    Transmission by Blood Transfusion:

    • Unknown

    Cases/Frequency in Population:

    • In the CFS study referred to above, 3.7% of healthy controls
    harbored viral DNA sequences in PBMCs; however, the
    expression pattern of viral genes in the infected controls
    appeared to differ from those among the CFS population so
    the relevance of the observation must be explored.

    Incubation Period:

    • Unknown

    Likelihood of Clinical Disease:

    • Unknown

    Primary Disease Symptoms:

    • If causal relationships are confirmed, symptoms will be
    those of the associated diseases.
    Many prostate cancers are asymptomatic, but symptoms
    of urinary obstruction and metastatic spread
    occur with advancing disease.
    CFS (also called, more descriptively, myalgic encephalitis)
    is characterized by persistent or recurrent fatigue,
    diffuse musculoskeletal pain, sleep disturbances, and
    subjective cognitive impairment of 6 months duration
    or longer. Symptoms are not caused by ongoing exertion,
    are not relieved by rest, and result in a substantial
    reduction of previous levels of occupational, educational,
    social, or personal activities. Alterations of
    immune, neuroendocrine, and autonomic function
    may be associated with this syndrome, but none
    is diagnostic. There is considerable overlap between
    this condition, fibromyalgia, and some affective
    disorders.

    Severity of Clinical Disease:

    • The original cohort of prostate cancer patients harboring the
    homozygous mutation in the RNase L gene had aggressive
    prostate cancer. The strength of this association will require
    more investigation.
    • CFS produces very significant disability with substantial disruption
    of activities of daily living among those meeting
    strict case definitions.

    Mortality:

    • Unknown, but XMRV has been associated with a more
    aggressive form of prostate cancer in one study that awaits
    Confirmation

    Chronic Carriage:

    • Chronicity is a feature of the Retroviridae family

    Treatment Available/Efficacious:

    • Unknown.

    Agent Specific Screening Question(s):

    • No specific question is in use for blood donors and is not
    indicated because transfusion transmission has not been
    demonstrated.
    • No sensitive or specific question is feasible.
    The high apparent prevalence of infection reported in
    healthy control subjects and the high prevalence of
    chronic fatigue in the population are expected to make
    donor history screening unreliable.
    The rate at which potential donors carrying a criteriabased
    diagnosis of CFS present to donor centers is
    unknown, but probably low in light of the associated
    disability.

    Laboratory Test(s) Available:

    • No FDA-licensed blood donor-screening test exists.
    • Standards for the diagnosis of XMRV infection have not been
    established.
    • Research assays include PCR, cell culture, flow cytometrybased
    immunoassay, and immunohistochemical analyses.

    Currently Recommended Donor Deferral Period:

    • No FDA Guidance or AABB Standard exists for blood
    donors.
    • Current practice is to accept donors who are healthy at the
    time of donation.
    • Pending the availability of further data, prudent practice
    would be indefinite deferral of donors who have received a
    diagnosis of XMRV infection.

    Impact on Blood Availability:

    • Agent-specific screening question(s): Not applicable
    • Laboratory test(s) available: Not applicable

    Impact on Blood Safety:

    • Agent-specific screening question(s): Not applicable
    • Laboratory test(s) available: Not applicable

    Leukoreduction Efficacy:

    • The initial studies in CFS suggest there is plasma viremia, so
    leukoreduction is unlikely to be completely effective.

    Pathogen Reduction Efficacy for Plasma Derivatives:

    No specific data are available but presumed to be robust as the
    agent is an enveloped virus that should be sensitive to many
    measures used in the fractionation process.

    Other Prevention Measures:

    • Unknown

    Suggested Reading:

    1. Coffin JM and Stoye J P. Perspectives: A new virus for old
    diseases? Science. 2009;326:530-1.
    2. 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;104:
    1655-60.
    3. 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;43:277-83.
    4. 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;
    6:92.
    5. Hong S, Klein EA, Das Gupta J, Hanke K, Weight CJ,
    Nguyen C, Gaughan C, KimKA, Bannert N, Kirchhoff F,
    Munch J, Silverman RH. Fibrils of prostatic acid phosphatase
    fragments boost infections with XMRV (xenotropic
    murine leukemia virus-related virus), a human retrovirus
    associated with prostate cancer. J Virol. 2009;83:6995-
    7003.
    6. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R,
    Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto A,
    Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards
    BK (eds).
    SEER Cancer Statistics Review, 1975-2006, National
    Cancer Institute. Bethesda, MD. http://seer.cancer.gov/
    csr/1975_2006/. Accessed November 5, 2009.
    7. 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, Mikovits JA. Detection of an
    infectious retrovirus, XMRV, in blood cells of patients with
    chronic fatigue syndrome. Science 2009;326:585-9.
    8. 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;106:16351-6
    9. Silverman RH. A scientific journey through the 2-5A/RNase
    L system. Cytokine Growth Factor Rev. 2007;18:381-8.
    10. Smith WR, Noonan C, Buchwald D. Mortality in a cohort
    of chronically fatigued patients. Psychol Med. 2006;36:
    1301-6.
    11. The Universal Virus Database, v3. http://www.ncbi.nlm.nih.
    gov/ICTVdb. Accessed November 4, 2009.
    12. 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 RNASEL variant. PLoS Pathog. 2006;2:e25.
  2. bullybeef

    bullybeef Senior Member

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    North West, England, UK

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