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Neurologic disease induced by polytropic murine retroviruses

Discussion in 'XMRV Research and Replication Studies' started by natasa778, Jan 22, 2010.

  1. natasa778

    natasa778 Senior Member

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    Neurologic disease induced by polytropic murine retroviruses: neurovirulence determined by efficiency of spread to microglial cells

    Several murine leukemia viruses (MuLV) induce neurologic disease in susceptible mice. To identify features of central nervous system (CNS) infection that correlate with neurovirulence, we compared two neurovirulent MuLV, Fr98 and Fr98/SE, with a nonneurovirulent MuLV, Fr54. All three viruses utilize the polytropic receptor and are coisogenic, each containing a different envelope gene within a common genetic background. Both Fr98 and Fr98/SE induce a clinical neurologic disease characterized by hyperexcitability and ataxia yet differ in incubation period, 16 to 30 and 30 to 60 days, respectively. Fr54 infects the CNS but fails to induce clinical signs of neurologic disease. In this study, we compared the histopathology, regional virus distribution, and cell tropism in the brain, as well as the relative CNS viral burdens. All three viruses induced similar histopathologic effects, characterized by intense reactive astrogliosis and microglial activation associated with minimal vacuolar degeneration. The infected target cells for each virus consisted primarily of endothelial and microglial cells, with rare oligodendrocytes. Infection localized predominantly in white matter tracts of the cerebellum, internal capsule, and corpus callosum. The only feature that correlated with relative neurovirulence was viral burden as measured by both viral CA protein expression in cerebellar homogenates and quantification of infected cells. Interestingly, Fr54 (nonneurovirulent) and Fr98/SE (slow disease) had similar viral burdens at 3 weeks postinoculation, suggesting that they entered the brain with comparable efficiencies. However, spread of Fr98/SE within the brain thereafter exceeded that of Fr54, reaching levels of viral burden comparable to that seen for Fr98 (rapid disease) at 3 weeks. These results suggest that the determinants of neurovirulence in the envelope gene may influence the efficiency of virus spread within the brain and that a critical number of infected cells may be required for induction of clinical neurologic disease. J. Virol., Jul 1997, 5287-5294, Vol 71, No. 7, SJ Robertson, KJ Hasenkrug, B Chesebro and JL Portis,Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA.

    http://jvi.asm.org/cgi/content/abstract/71/7/5287
     
  2. Good find, thank you.

    I'd like to see what Abjhit Chaudhuri (British Neurologist with a keen interest in ME) finds in the coming years regarding neurological disease findings in ME - and the new finding of XMRV in humans.

    He found something like Astrocytes (Glial Cells) which were indicative of inflammation, I can't remember specifically. In the talk he gave, he mentioned it showed immune activity, but there was no direct evidence of a virus found in the brain studied. That was 4/5 years ago though, before XMRV was known about or able to be detected.

    On a personal note it's so frustrating to have a 'neurological disease' (ME) that affects the brain so obviously: cognition/memory problems/dysautonomia/gait change etc etc - yet have no acceptance of this by the scientific community in general.

    Yet, when one can see research that hints in a mouse model, or links to what patients 'feel' but cannot show - those feelings briefly turn from being frustrating to being a bit shocking.
    .
    It won't surprise me at all,if within 10 years (or less), it's announced by previous uninterested scientists, that XMRV infects/causes brain cell death, inflammation and 'brain disease'.

    It may take 30 years to get that far, but I imagine that day will come, and it won't be a nice one, even if we feel the 'disability' of brain dysfunction (possibly disease) already.
     
  3. natasa778

    natasa778 Senior Member

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    H
    same findings in autism... interesting that Vargas/Pardo postmortem study found extremely high levels of MCP-1 cytokine in asd brains compared to controls (many other inflammatory markers were also raised, by none as bad as mcp-1 increase, which was 12-fold).

    and now this:
    MCP-1 and CCR2 Contribute to Non-Lymphocyte-Mediated Brain Disease Induced by Fr98 Polytropic Retrovirus Infection in Mice: Role for Astrocytes in Retroviral Neuropathogenesis http://jvi.asm.org/cgi/content/abstract/78/12/6449
     
  4. natasa778

    natasa778 Senior Member

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    this study by the same time found retroviral damage to brain without it infecting neurons directly and without lymphocytes entering the brain, but solely through activation of microglia/astrocytes and overexpression of cytokines:

    Thus, astrocytes, previously not thought to play an effector role in the disease process were found to contribute to pathogenesis through the production of MCP-1. This study also demonstrates that chemokines can mediate pathogenesis in the CNS in the absence of lymphocytic infiltrate and gives credence to the hypothesis that chemokine upregulation is a mechanism by which retroviruses such as human immunodeficiency virus induce neurological damage.
    http://jvi.asm.org/cgi/content/full/78/12/6449
     
  5. Oh. My. Days. This is huge!

    :eek::eek::eek:

    This makes so much sense in the light of Autistic kids testing + for XMRV and CNS damage in ME too.

    Thanks Natasa!!

    -Rachel xx
     
  6. Thanks for that Natasa.

    So we know, that Autism may be linked to XMR too.....

    Also you mentioned Cytokines. My little mind remembers something to do with 'Brain Cytokines' being elevated in ME patients, I think this was Dr Kerr who mentioned this in a paper somewhere but I cannot recall where when I read it. I'm sure that Nancy Klimas in her XMRV talk said something about brain inflammation too.

    Your last post mentioned: MCP-1 Cytokine in brains. MCP-1 Cytokine can be tested for in Europe from RedLabs as part of an Inflammatory Cytokine panel.

    Still on the Cytokine theme and retroviruses from Fletcher et al, November 2009.
    Plasma cytokines in women with chronic fatigue syndrome
    Source: Link

    ''The observations of abnormal cytokine patterns in CFS patients support the reports of retrovirus infections and reactivation of latent herpes virus infections. DeFreitas, et al found HTLV-II- like gag sequences by polymerase chain reaction and in situ hybridization as well as antibodies reactive with human T- lymphotropic virus (HTLV) in a majority of 30 CFS cases. Twenty healthy controls were negative for the three assays [11]. Holmes, et al, reported that structures consistent with stages of a Lentivirus replicative cycle were observed by electron microscopy in 12-day PBMC cultures from 10 of 17 CFS patients and not in controls [12]. Recently, DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), was found in the PBMC of 68 of 101 patients compared to 8 of 218 healthy controls. Patient-derived, activated PBMC produced infectious XMRV in vitro. Both cell associated and cell-free transmission of the virus to uninfected primary lymphocytes and indicator cell lines was possible [13]. The XMRV gag and env sequences discovered in CFS cases were more than 99% similar to those previously reported for prostate tumor-associated strains of XMRV [29].''
     
  7. bullybeef

    bullybeef Senior Member

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    If they knew this in 1997, what do they know now?

    I have a suspicion that Mikovits and Co know exactly what XMRV is doing, and now I am even more convinced.
     

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