XMRV Xenotropic Murine leukemia virus

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XMRV Xenotropic Murine leukemia virusRelated
Virus linked with CFS true or not true

• Anders Widell, MD, PhD, Lund University, Malmö
  University Hospital, Malmö, Sweden

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Xenotropic Murine Leukemia Virus Related Virus

• Xenos Greek Stranger (e.g. compare with
  Xenofobia)
• Xenotropic Murine. Infect others than mice,
  whereas ecotropic infects, polytropic broader
  mice and men
• MLV and XMRV are related gammaretroviruses, known
  for for long times.
• Belong to Gammaretroviruses

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The Retrovirus Family
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XMRV and suggested link to prostate cancer

• RNaseL linked cancer
• Confirmed by one other group
• Not confirmed by several other groups

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XMRV surfaces

• Lombardi et al in in Science 2009 describe a
  strong association 68 pos /101 tested between
  Chronic Fatigue Syndrome and presence of XMRV in
  CFS patients PBMCs
• Low prevalence in (3,7 ) healthy persons
• Dataset provided in Science paper
• XMRV nucleic acid by RT-PCR in PBMC
• XMRV antigens by Western in PBMCs
• XMRV T and B cells,
• 50 pts produce NT antibody
• Transferrable virus to Prostate Cancer cell line.
  EM

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Subsequent attempts to confirm Lombardis findings

• Several groups assess CFS patients using same
  techniques
• Hong et al 0/85 Chinese CFS patients positive
• Van Kuppeveld et al Dutch CFS patients
• Groom et al 0/299 patients, half of them with
  CFS,
• Heinrich et al 0/32 with CFS, nor in several
  other immune suppressed patient groups incl. HIV
• Tang et al 0/199 African patients with HIV
• Barnes et al 0/230 patients with HIV or HCV
• No confirmation

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Then a possible confirmation by Lo et al in PNAS

• MLV-like virus gag gene sequences LV in 41
  PBMC-derived DNA samples from 37 patients meeting
  accepted diagnostic criteria for CFS, in 32 of 37
  (86.5) compared with only 3 of 44 (6.8) healthy
  volunteer blood donors.
• Sequences retained over 15 years

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Criticism Sato et al

• When CFS patients were assessed, also water gave
  MLV like sequences
• Was found to be associated with RNA in Invitrogen
  Platinum hot start mouse monoclonal against the
  polymerase
• Very closely related to Los MLV like sequences
  Lo used Platinum

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Criticism - Hué et al

• XMRV sequences identical with retroviral
  sequences found in prostate cancer cell line
  22Rv1
• XMRV specific primers amplify several cell line
  associated MLVs
• Many tumour call lined have been established vi
  grafts in mice who have plenty of MLVs

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Figure 2 Phylogeny of 22Rv1 and patient derived
XMRV sequences and other murine leukaemia
viruses. Bayesian maximum clade credibility
phylogeny of 22Rv1 cell line derived XMRV
clones, patient derived XMRV sequences and other
murine leukaemia viruses (A). The monophyletic
cluster formed by 22Rv1 cell line derived XMRV
clones and patient derived XMRVs is magnified in
(B). Xenotropic MLV (MLV-X), polytropic MLV
(PMLV), and modified polytropic MLV (MPMLV)
were added as controls. Sequence s derived from
prostate cancer patients (VP and WO) and chronic
fatigue syndrome patients (WPI) are indicated by
red and y ellow circles respectively. Gene
sequences derived from 22Rv1 clones are
indicated by blue squares. When full-length
genomes were not available, the loci of the
sequence used in the phylogenetic reconstruction
are shown in brackets. APOBEC-3G/F hypermutated
clones are labelled with a closed circle. The
tree is rooted against AKV and Moloney MLVs .
Bayesian posterior probabilities of 1.00 are
indicated on the corresponding branches by a
star. The scale bar represents the number of
nucleotide substitutions per site.
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Lessons to learn

• Virus discovery and senstive PCR certainly can
  generate new viral sequences
• No molecular enzyme is completely free from
  production or stabilizing nucleic acid
• No statistical significance beats easy
  confirmation from independent investigators
• Earlier lessons from hepatitis non-A, non-B/HCV
• several systems appeared, got applauses and
  quietly disappeared
• and then came Chiron whose data could
  immediately be confirmed and generate BIG money
• Industrys living dream since then, GBV, TTV,
  SENV, XMRV

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Further lessons

• Do not exclude an infectious mechanism for CFS
  it may need other technology
• Be suspicious if the Discoverer only keeps
  presenting his/her original data over and over
  again adding nothing new he/she has had a good
  lead to generate more
• You can fool some of the People all the time,
  and all the People some of the Time, but never
  All the People All the Time /Churchill