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How acute viral infections can persist

Discussion in 'Other Health News and Research' started by anciendaze, Oct 6, 2017.

  1. anciendaze

    anciendaze Senior Member

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    This report at Medical Express is much more solid research than the continuing stream of medical articles suggesting psychobabble may be effective in treating poorly defined conditions. The caution here is that it concerns in vitro studies. What it does show is that some infected cells with many copies of defective viral genomes can persist when apoptosis destroys other cells which have only copies of the reference viral genome.

    This, in turn, points to a mechanism for prolonged immune activation following an acute viral infection. It also gives a plausible reason that testing for a particular viral sequence would fail to find these cells: surviving cells do not have the same genome as in the acute phase of viral infection.

    One thing which surprised me here was that all the named viruses are single-strand RNA viruses, which are notoriously unstable. This has led researchers to concentrate on the acute disease phase and neglect possible chronic conditions resulting from these. The acute diseases can be lethal, and I believe one brother of mine died of HRSV in his first year of life.

    Surviving infected cells avoid apoptosis and become strong stimulators of antiviral immune response. This could be the cause of persistent respiratory problems in patients who survive acute HRSV infection, since there are a lot of different respiratory viral infections possible, but would also offer some degree of immunity to similar viruses which might be lethal.

    We are still a long way from application to human medical treatments, but the hypothesis of a chronic state of peculiar antiviral immune response following an acute viral infection with "flu-like symptoms" should not be dismissed as patient imagination.

    I will also point out that major pandemics commonly involve more than one infectious agent. The virus for which the outbreak is blamed may only be one of several active in the patient population. Since HRSV was only discovered in infants in 1956 it is unlikely that anyone was looking for it in adults during the Asian flu epidemic of 1957, which was "the worst flu of my life". Because my brother had died of a characteristic infection just before the RSV virus was discovered, I could quite plausibly have been exposed prior to the time the Asian flu (H2N2) reached the U.S.

    Incidentally, my father, who had survived the Spanish flu (H1N1) as an infant, was not affected by the Asian flu. Nor were several other family members alive at the time (1918). Those born too late to be exposed were strongly affected. He seems to have had a persistent antiviral response almost 40 years after exposure. Up until now this kind of thing has been hard to explain for viruses as changeable as influenza.
     
    Last edited: Oct 6, 2017
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  2. Hip

    Hip Senior Member

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    The defective viral genomes (DVGs) that this article talks about I think may be of the same class as the non-cytolytic enteroviruses (aka defective enteroviruses) found in ME/CFS patients.

    Dr John Chia and others think that persistent infections with defective enteroviruses (which live inside human cells) may play a major role in ME/CFS.

    Some info about non-cytolytic enteroviruses / defective enteroviruses is given in this post.


    Another virus that uses defective viral genomes to help maintain the infection is dengue virus: see this article.

    Interestingly, after acute dengue infections, sometimes a post-infectious fatigue syndrome appears (ref: 1), which may relate to the fact that dengue can produce persistent infections with defective dengue viruses.

    Hepatitis B and hepatitis C are two others virus that produce defective viral infections, and again, chronic infections with these viruses results in fatigue as a major symptom.

    And Ebola virus produces defective viral infections, and Ebola survivors often suffer long term extreme fatigue.
     
    Last edited: Oct 8, 2017
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  3. Hip

    Hip Senior Member

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    In terms of trying to fight defective virus infections inside cells, this paragraph from the article is of interest:
    So if you want the immune system to kill cells infected with a defective virus, conceivably inhibiting the MAVS pathway might achieve this.
     
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  4. halcyon

    halcyon Senior Member

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    This appears to be what might happen in enteroviral ME, though the evidence is limited and we can't yet show that the patient mutated the virus in this way, vs. being infected with the mutant from the start. It was shown in this paper:

    [​IMG]

    This is why it's important to know what part of the viral genome researchers (such as Ron Davis) are targeting with their bespoke PCR primers. Their primers may miss a mutated section of the genome and result in a false negative.
     
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  5. Jesse2233

    Jesse2233 Senior Member

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    @halcyon that is an excellent point on PCR missing viral mutations. If that's the case, how might researchers adjust what they're looking for without knowing what the new mutation is?
     
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  6. Jesse2233

    Jesse2233 Senior Member

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    Might this explain why some have chronically high TNF levels? and how might MAVS be inhibited using existing treatments?
     
  7. halcyon

    halcyon Senior Member

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    If they can isolate a genome from a sample, I assume they can sequence it and compare to wild type virus to find a sequence that isn't mutated and make sure their primer targets that segment.
     
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  8. Hip

    Hip Senior Member

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    I did briefly search for drugs or supplements that might inhibit the mitochondrial antiviral-signaling (MAVS) protein, but could not find anything.

    Although it seems coxsackievirus B itself inhibits MAVS, as an immune evasion tactic: this paper finds that an enzyme made by CVB called 3C cysteine proteinase is able to cleave (chop into bits) the MAVS protein, thereby disabling MAVS signaling.

    However, this later paper contradicts this, and says that MAVS is actually cleaved by the CVB enzyme 2A.



    In any case, if CVB is itself inhibiting MAVS by either its 3C or 2A viral enzymes in order to evade the immune response, that suggests perhaps MAVS inhibition using a drug would actually promote rather than thwart this virus.

    Incidentally, the drugs glyceryl trinitrate (nitroglycerin) and isosorbide dinitrate (which convert into nitric oxide in the body) inhibit 3C and 2A, which in turn should increase MAVS in CVB-infected cells. See this study.

    One ME/CFS patient (@zzz) entered full remission for 8 years after taking just one single 10 mg dose of isosorbide dinitrate (with no further drugs required, so this was like a proper cure). See this thread.
     
    Last edited: Oct 7, 2017
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  9. anciendaze

    anciendaze Senior Member

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    Note that the form of immune activation these researchers are talking about is different from ordinary defense via a limited range of antibodies. A surviving infected cell may even be continuing to produce new variants over time.

    This is why I mentioned the speculation about my father's, (and several other family members',) apparent immunity to the Asian flu due to early exposure to the Spanish flu. One thing which made that Asian epidemic worse was that vaccines for H1N1, which was also present in some places experiencing that epidemic, did not do much to protect against H2N2. Typical acquired immunity is narrowly specific, and probably not as long lasting as 40 years. There are certainly other explanations, but this kind of anomaly has nagged at me for a long time.

    I will also point out that this kind of behavior takes place with retroviruses, which typically leave large numbers of defective copies around.
     
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  10. Hip

    Hip Senior Member

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    The paper published by these researchers is this one.

    I had a look at the full paper, and it does not seem to state whether these DVGs are naked strands of viral RNA that live within cells, as the defective enterovirus do (defective enteroviruses are not full viral particles, but just strands of naked viral RNA that live and replicate within cells), or whether these DVGs are full viral particles.
     
  11. anciendaze

    anciendaze Senior Member

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    @Hip

    My understanding was that they were not finding full viral particles because these were not lytic infections. This also seems related to the hypothesis that Dr. A. Martin Lerner described in terminology that many people failed to understand: “CFS is a persistent nonpermissive herpes virus infection of the heart”. We still haven't pinned down the role of herpes-type viruses like HHV-6a or direct infection of heart tissue, but persistent infections still seem quite relevant. A non-permissive viral infection does not allow efficient production of virions and resulting viremia. It can still push the immune system into a persistent state as long as infected cells survive.

    It is entirely possible those patients who did not respond to Dr. Lerner's antiviral therapy did not have the problem with herpes-type viruses he was postulating.

    This new work opens up the possibility that persistent infections can involve single-strand RNA viruses normally considered too unstable to persist for years in living hosts.

    Here's a random find from a search on nonpermissive viral infections. Anything about this sound familiar?
     
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  12. Hip

    Hip Senior Member

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    Seems that there are three types of slow "smoldering" viral infections (as far as I am aware):

    (1) Non-permissive viral infections. These appear to be caused when a virus infects a cell type that it normally cannot properly replicate in. This article says that non-permissive cells may lack the receptors need for viral entry, or may lack factors required for a complete replication cycle. In the latter case, an abortive infection may occur, in which virus replication begins but does not result in the production of progeny virus. The term semi-permissive refers to a cell in which a small yield of progeny virus may be produced.

    (2) Latency states in which there is restricted viral reactivation. An example is the three latency states of Epstein-Barr virus. And Dr Kazuhiro Kondo thinks there may be three latency states of HHV-6.

    (3) Non-cytolytic viral infections, in which RNA from the viral genome starts to replicate without creating any viral particles or viral capsids, and lives within cells as a long term intracellular infection.
     
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  13. duncan

    duncan Senior Member

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    That we know of. It may be enterovisuses are it. I hope so.

    @Hip, could what we call ME/CFS be a poor generic description of symptoms that could be caused by more than one pathogen? Could ME/CFS just be a symptomatic shorthand for a group of pathogens - or even singularly - that cause a similar or degreed "disease"?
     
    Last edited: Oct 9, 2017
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  14. Hip

    Hip Senior Member

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    I think most researchers that study infection etiologies of ME/CFS would probably agree that more than one pathogen is able to cause ME/CFS. So then the question is, what do the pathogens that can cause ME/CFS all have in common, such that they can give rise to ME/CFS?

    After all, certain viruses never trigger ME/CFS. Have you ever heard of ME/CFS appearing after norovirus infection? Or adenovirus infection? I've never come across such cases. So these viruses don't possess that special factor that triggers ME/CFS. But viruses like coxsackievirus B, echovirus and Epstein-Barr virus do possess that factor.
     
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  15. duncan

    duncan Senior Member

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    Yes.

    I know you know the greater medical community is not structured to deal with chronic diseases. We simply don't know what the f*ck to do with tertiary or late stages.
     
    Last edited: Oct 10, 2017
  16. duncan

    duncan Senior Member

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    As I recall, pathogens MAY persists, many in tissue vs blood. Anyone care to remember how Lipkin warned against tissue testing?
     
    Last edited: Oct 10, 2017
  17. Hip

    Hip Senior Member

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    I did not heard about that. What did Prof Lipkin say?
     
  18. duncan

    duncan Senior Member

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    This is going back to the xmrv thing, if I recall correctly, so I do not remember exactly. But I seem to remember him warning against testing tissue. Eh, my memory is full of holes, so perhaps I have this wrong.

    To adequately test for pathogens, though, I would think tissue sampling would be essential - especially with some of the diseases we are entertaining.
     
  19. anciendaze

    anciendaze Senior Member

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    Humans are likely to harbor a range of persistent viral infections that generally don't cause lethal disease. This is not exactly news. The problem comes from equating "not rapidly lethal" with "benign". Take a look at the early history of M.E. naming, and you will find it was originally described as "benign" until Ramsey realized that patients were being long-term disabled. If you are careless with terminology you could class poliomyelitis, which kills only a tiny percentage of those infected, as "benign" -- even if it leaves surviving patients in an iron lung. Falling short of that extreme is no trivial matter. My mother lived a long life, but suffered a great deal due to post-polio syndrome. Her response to that infection should not be classed as "benign" either.

    There has already been talk that EBV stimulates general immune response, so removing it would be unwise. This mechanism for persistent immune activation may be involved, but so far we don't know, and this is one of the most common viruses in humans. If the patient is suffering from a condition involving inappropriate immune activation, treating such a persistent infection is a reasonable idea, even if it might not be for a random member of the general population who is not experiencing any particular impairment.

    At the moment we don't have reliable ways of telling what the immune system is doing unless we are dealing with acute infections, some cancers or a few autoimmune diseases. This is not acceptable in the long term. Doctors need to start treating individual patients for conditions they are actually experiencing, not for conditions that the doctor imagines some generic patient might have. No matter how many other people have some other problem, the patient in front of you does not necessarily have the same thing.

    I've stated this differently when talking about people I know with a serious genetic disease that shows up once in 100,000 live births. Does the fact that this is rare absolve the doctor if he pulls out a gun and shoots the patient to simplify his own practice?
     
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