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Research suggests viral infection could underlie some symptoms of brain disorders

Discussion in 'Other Health News and Research' started by Ecoclimber, Dec 5, 2015.

  1. Ecoclimber

    Ecoclimber Senior Member

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    Penn Study Shows that Certain Herpes Viruses Can Infect Human Neurons

    Research suggests viral infection could underlie some symptoms of brain disorders

    PHILADELPHIA - For years, researchers have noted a tantalizing link between some neurologic conditions and certain species of the herpes virus. In patients with Alzheimer’s disease, multiple sclerosis, and cerebellar ataxia, among other neuropathies, the cerebrospinal fluid teems with Epstein-Barr virus (EBV). Yet, the nature of that link has remained unclear, as it has been assumed that EBV, as well as other viruses in the same sub-family, called gammaherpesviruses, cannot infect neurons.

    Now, thanks to investigators from the Perelman School of Medicine at the University of Pennsylvania, researchers in this field know better. Erle S. Robertson, PhD, a professor of Microbiology and Otorhinolaryngology and Director of the Tumor Virology Training Program at the Abramson Cancer Center, and colleagues published in mBio this week that EBV and a related virus, Kaposi’s sarcoma-associated herpesvirus (KSHV), can infect and replicate in both cultured and primary neurons.

    Though by no means proving causality, those data do suggest viral infection could underlie at least some of the symptoms of those brain disorders, as well as the potential utility of antiviral drugs as a novel therapeutic strategy.

    According to Robertson, several lines of evidence suggested the possibility that gammaherpesviruses could infect brain tissue. First, the viruses are enriched in the cerebrospinal fluid and brain tissue of individuals with such conditions as multiple sclerosis (MS) and Alzheimer’s disease. In addition, individuals with a history of infectious mononucleosis caused by EBV are more likely to develop MS, while those who have never been infected with EBV are less likely to do so. Particularly tellingly, the drug acyclovir, which can inhibit EBV and related viruses, has been examined as a potential treatment for MS, with some positive, albeit inconclusive, results.

    Still, says Robertson, the ability of gammaherpesviruses to infect neurons has been “controversial.” Devan Mehta, a student in Robertson’s lab, working with postdoctoral fellow Hem C. Jha, PhD, and Dennis Kolson, MD, PhD, a professor of Neurology, tested the link directly. Using genetically modified viruses that express green fluorescent protein (GFP), Mehta infected human neuroblastoma cells (neurons differentiated from cancer cells) and primary human fetal neurons, monitoring the infection over time by microscopy and protein expression.

    In both cell types, infection with either EBV or KSHV resulted in the appearance of a fluorescent signal in the infected cells, as well as the appearance of key viral proteins. The media in which infected cells were grown also contained functional virus particles capable of infecting other cells, indicating a mode of infection that tears open host cells. On the other hand, treatment of infected cells with acyclovir reduced the production of virus particles.

    “I couldn’t believe it,” Robertson said. “After 50 years of studying EBV, nobody had ever seen the virus in nerve cells. But maybe they just never looked.”

    According to Robertson, these data suggest that viral infection of neurons could be associated with neuropathology, though he emphasizes that it is not the same as establishing causality. Such proof, if it ever comes, could be years away.

    “There’s likely to be association of this virus with neurons,” he stated. “But more studies will be necessary to know whether it is actually associated with disease pathology.

    Why EBV and KSHV infection of neurons results in a specific destructive form of infection will also be explored in future research. In contrast, when these viruses infect other cell types, such as B cells, they enter a latent mode, in which virus particles are relatively dormant. But, when they infect neurons, the particles apparently direct the cells to produce large amounts of virus, burst, and die, which explains why the growth media bathing infected cells could be used to infect other cells. “That’s an interesting twist,” Robertson said.

    If nothing else, the ability of gammaherpesviruses to infect neurons provides a new model system for studying viral life cycles. But these viruses ultimately may also prove useful in studying disease etiology. “If you can infect nerve cells, that’s likely to have some sort of pathology,” he said.

    Additional authors include Jie Lu, Darine El-Naccache, Sanket K. Shukla and Colleen Kovacsics, all from Penn.

    The study was funded by the National Cancer Institute (R01-CA- 137894, R01-CA-171979, R01-CA-177423, CA-137894-05, P30-DK- 050306, and P01-CA-174439), the Leukemia & Lymphoma Society, and the Abramson Cancer Center.
     
  2. Hip

    Hip Senior Member

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    Very interesting. So EBV and HHV-8 (Kaposi's sarcoma-associated herpesvirus) may be able to infect neurons in the brain, if this study pans out.

    Herpes family virus infections of the brain are certainly not unknown: HHV-6 can infect astrocyte cells in the brain, and temporal lobe epilepsy is associated with HHV-6 infection of astrocytes.

    Also, herpes simplex virus 1 infection has been found in the brain tissues of Alzheimer's patients, which some researchers suggesting this may be a causal factor in this disease (one study found that HSV-1 infection leads to a dramatic increase in beta-amyloid plaque).

    Enteroviruses can also infect the brain tissues, and three separate brain autopsies on deceased ME/CFS patients have found enterovirus / coxsackievirus B infection in the brain tissues, which was not found in any of the controls (see this post for details of these ME/CFS brain autopsies).



    It will great when more ME/CFS postmortem brain autopsy studies are done, to see which viruses might be infecting neurons and other types of brain cell such as astrocytes.

    There have been calls for some years now regarding setting up an ME/CFS post mortem tissue bank, which would be able to perform brain autopsies that could test for viral infections in the brain. However, the high cost of setting up such a facility has been the stumbling block.
     
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  3. anciendaze

    anciendaze Senior Member

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    Please note that while an initial EBV infection is associated with mononucleosis/glandular fever, thereafter the usual course is that the virus remains latent in cells for life. HHV-8/KSHV infection was discovered in connection with AIDS and HIV. Both of these suggest immune dysfunction which stops short of the complete collapse found in AIDS.

    I would also point out that common tests do not go into great detail to distinguish strains of EBV, and they certainly do not look for particular strains of EBV in the brain. In addition to the viruses mentioned above, there is good reason to look for HHV6 and VZV. There is no question that VZV can infect neurons, and reemerge many years after initial infection. When that happens the disease is called shingles.

    One can also draw parallels with MDV in fowl, a gamma-herpes-type virus with structural similarities to VZV and other HHVs. Marek's disease not only involves lymphomas, immunosuppression and nerve damage, it also leads to atherosclerosis. This means there are at least four parallels to major human diseases on which a great deal of research has been done without substantially reducing incidence.

    Why are we just now finding out such fundamental facts about common viruses in humans?
     
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  4. Ecoclimber

    Ecoclimber Senior Member

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    Premission to repost by Prof. Gavin Giovannoni

    There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

    Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.


    I have to report that the Charcot Ptoject using Valtrex on a patient cohort failed. This was to test the hypothesis that EBV was a trigger for Multiple Sclerosis. Gavin Giovannoni: The Inspire Study took less than 7 years to complete. The study was negative in terms of the primary outcome. We will be presenting the results in a full at a scientific meeting next year. The reference trial information is located here: http://multiple-sclerosis-research.blogspot.com/p/charcot-project.html

    There is another trial to test the hypothesis that MS could be trigger by a HERV. Patients are receiving raltegravir (Isentress). The trial is being funding through crowdsourcing and is ongoing.
     
    Last edited: Dec 19, 2015
  5. ScottTriGuy

    ScottTriGuy Stop the harm. Start the research and treatment.

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    Toronto, Canada
    Interesting - I started Isentress just over 2 weeks ago - so far a lot more sleepiness, but not as bad as the first few days - I'm sleeping better at night - my PEM threshold has yet to move though - I'm trying to be patient.
     
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  6. natasa778

    natasa778 Senior Member

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    Failed trial does not disprove this particular hypothesis of EBV acting as a trigger, as you would not expect a treatment of the initial trigger/s to have much bearing on the disease years later... It can only (and only to a certain degree) show that EBV as we know it, the Valtrex-responsive EBV, is not the pathological driving force in these cases.
     
  7. Ecoclimber

    Ecoclimber Senior Member

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    Actually there were two trials ongoing at the same time. There was an embargo in place until published. There were hints suggesting one vs. the other. One was to determine that EBV could possibly be the trigger for MS and the other on whether a retrovirus was a trigger for MS.


    Premission to repost by Prof. Gavin Giovannoni

    There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

    Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.

    When you are down and being kicked what do you do? By Gavin Giovannoni


    "As you are probably aware by now the INSPIRE (Raltegravir) trial was negative regarding its primary outcome; raltegravir had no impact on MRI activity in this cross-over study design. We have some biomarker data, independent of the action of raltegravir or the study design, that we will be presenting at a meeting sometime this year (observational data). We are in the process of completing the end of trial report and tying up loose ends. Once we have done this we will be submitting a paper for publication on the negative trial results."

    "We have been taking quite a kicking from internet trolls about this study; there are clearly people out there who don't like us and are very against the viral hypothesis of MS and the Charcot Project. However, I was inspired last night by several very kind, and inspiring comments, that some of you posted; particularly the Robert Kennedy quote. Thank You, your support is much appreciated."


    'Only those who dare to fail greatly can ever achieve greatly.' - Robert F. Kennedy
    "We are therefore definitely not giving-up on the Charcot Project and plan to focus our attention this year on EBV as the trigger and driver of MS disease activity. We have therefore taken your advice and have launched a small Crowdfunding campaign to raise money to provide data for us to test whether or not an old antiviral drug is capable of suppressing lytic EBV infection in pwMS and to find the correct dose of the drug to use in a clinical trial. Before applying for funding for these studies we need to ascertain how many pwMS are shedding EBV in their saliva. The latter is required for us to power the study appropriately; in other words how many subjects will be required in the study to show that the drug works. We will be posting more on our proposed plans and will appreciate your input."

    "I hope you are still willing to support us! Thank You."


    IF

    BY RUDYARD KIPLING

    IF you can keep your head when all about you
    Are losing theirs and blaming it on you,
    If you can trust yourself when all men doubt you,
    But make allowance for their doubting too;
    If you can wait and not be tired by waiting,
    Or being lied about, don't deal in lies,
    Or being hated, don't give way to hating,
    And yet don't look too good, nor talk too wise:

    If you can dream - and not make dreams your master;
    If you can think - and not make thoughts your aim;
    If you can meet with Triumph and Disaster
    And treat those two impostors just the same;
    If you can bear to hear the truth you've spoken
    Twisted by knaves to make a trap for fools,
    Or watch the things you gave your life to, broken,
    And stoop and build 'em up with worn-out tools:

    If you can make one heap of all your winnings
    And risk it on one turn of pitch-and-toss,
    And lose, and start again at your beginnings
    And never breathe a word about your loss;
    If you can force your heart and nerve and sinew
    To serve your turn long after they are gone,
    And so hold on when there is nothing in you
    Except the Will which says to them: 'Hold on!'

    If you can talk with crowds and keep your virtue,
    ' Or walk with Kings - nor lose the common touch,
    if neither foes nor loving friends can hurt you,
    If all men count with you, but none too much;
    If you can fill the unforgiving minute
    With sixty seconds' worth of distance run,
    Yours is the Earth and everything that's in it,
    And - which is more - you'll be a Man, my son!

    Bottom line: EBV trial using Valtrex will be the next trial
     
    Last edited: Jan 6, 2016
    maryb and heapsreal like this.

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