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LJ-001: Antiviral for enveloped viruses (good news!)

Discussion in 'XMRV Testing, Treatment and Transmission' started by guest, Feb 19, 2010.

  1. guest

    guest Guest

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    LJ-001: New Antiviral for enveloped viruses

    Just came over this new article on virology.ws. LJ-001 blocks entry for XMRV too and is non toxic to the cell. Vincent is doing a great job with his blog, I'm very thankful. :Retro smile:

    http://www.virology.ws/2010/02/18/an-antiviral-for-enveloped-viruses/

    An antiviral for enveloped viruses
    by VINCENT RACANIELLO on 18 FEBRUARY 2010
    Broad spectrum antibiotics are available that act against a wide range of bacteria, including both gram-positive and gram-negative species. In contrast, our antiviral arsenal is exceedingly specific. Nearly all the known antivirals block infection with one or two different viruses. The discovery of a compound that blocks infection with many different enveloped viruses may change the landscape of antiviral therapy.

    A small molecule has been discovered that inhibits infection by a wide range of viruses with membranes, the so-called enveloped viruses. The compound, called LJ001, is a derivative of aryl methylene rhodanine. It was discovered in a search for compounds that block the entry of Nipah virus into cells. LJ001 was then found to block infection of cells by a wide variety of enveloped viruses, including filoviruses (Ebola, Marburg); influenza A virus; arenaviruses (Junin), bunyaviruses (Rift Valley fever virus, LaCrosse virus); flaviviruses (Omsk hemorrhagic fever virus, Russian spring-summer encephalitis virus, yellow fever virus, hepatitis C virus, West Nile virus); paramyxoviruses (Nipah virus, parainfluenza virus, Newcastle disease virus); retroviruses (HIV-1, murine leukemia virus); rhabdoviruses (vesicular stomatitis virus); and poxviruses (cowpox virus, vaccinia virus). The compound had no effect on viruses without an membrane, such as adenovirus, coxsackievirus, and reovirus.

    To determine which step of viral infection is blocked, LJ001 was added at different times during infection. Inhibition of infection was observed when LJ001 and virus were incubated before being added to the cell. However, if the virus was allowed to enter the cell, addition of the compound had no effect on the production of infectious virus. Inclusion of LJ001 into the culture medium did prevent virus spread to neighboring cells.

    LJ001 inhibits such a wide spectrum of viruses because it targets a feature common to all of them: the viral envelope (see image of influenza virus for an example). The compound blocks virus infection by inserting into the viral membrane and inhibiting entry into the cell. It does not block virus attachment to cells, but impairs fusion of the viral and cell membranes, a step essential for entry of the viral genome into cells. However, LJ001 is not toxic to cells, and does not inhibit the fusion of neighboring cells caused by some viral infections.

    How might LJ001 impair viral but not cellular membranes? One explanation is that the compound damages both viral and cell membranes. The latter can be repaired and consequently escape the toxic effects of the drug. In contrast, viral membranes are static, and once damaged by LJ001 they can no longer function properly during virus entry into cells.

    Whether LJ001 and derivatives will be useful for treating virus infections in animals awaits the results of testing in animal models and then in humans. Meanwhile, an interesting question is whether viral mutants resistant to LJ001 and its derivatives will emerge. Just because the drug targets a component derived from the host cell does not mean that resistance will not emerge. The drug brefeldin A, an inhibitor of poliovirus, blocks a cellular enzyme, yet viral mutants resistant to the drug have been identified. One possibility for the mechanism of resistance could be amino acid changes in viral glycoproteins that protect the viral membrane from damage caused by LJ001.

    Perhaps its not a matter of whether mutants resistant to LJ001 will emerge, but when they will be identified.

    Wolf, M., Freiberg, A., Zhang, T., Akyol-Ataman, Z., Grock, A., Hong, P., Li, J., Watson, N., Fang, A., Aguilar, H., Porotto, M., Honko, A., Damoiseaux, R., Miller, J., Woodson, S., Chantasirivisal, S., Fontanes, V., Negrete, O., Krogstad, P., Dasgupta, A., Moscona, A., Hensley, L., Whelan, S., Faull, K., Holbrook, M., Jung, M., & Lee, B. (2010). A broad-spectrum antiviral targeting entry of enveloped viruses Proceedings of the National Academy of Sciences, 107 (7), 3157-3162 DOI: 10.1073/pnas.0909587107
  2. omerbasket

    omerbasket Senior Member

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    Can we conclude from the fact that it's useful again Murine Leukemia Viruses, that it must be useful against XMRV?
  3. George

    George Guest

    XMRV is an envelope based virus and a really weeny envelope too! So yes it should work on XMRV. But it doesn't reduce current infection, it only keeps the virus from spreading by killing it off, via envelope inhibition. So your viral load doesn't go up. I don't know how effective it would be with our illness. It might be and I'm just going on bits and pieces here, that a lot of the damage to our system is caused from proteins that are manufacture by the virus.

    It's really exciting though isn't it???!!!!
  4. Abraxas

    Abraxas Senior Member

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  5. guest

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    Ye, it is exciting although I'm still hoping for a breakthrough.
  6. omerbasket

    omerbasket Senior Member

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    I don't understand something. They say that if you reduce the viral load of XMRV in ME/CFS (if it is the cause for ME/CFS), than it's possible that it would make you better or even much much better. As I understand it, the new study here says that LJ-001 can cause XMRV to not enter the cells (and therfore to be harmless, no?). So, offcurse, there is the XMRV that is already in the cell. But when it's in the cell - are there drugs today, let's say for AIDS, which does something to the virus that is already in the cell?
    And a more general question which regards this topic, and for a long time I wonder about, is: Let's say we have 1 cell with one retrovirus dna. We don't have any other retroviruses. Cells, as we now, duplicate (or is it replicate?). When a cell duplicate - does the new cell have the retrovirus DNA in it too, or is it clear of the retrovirus DNA untill another retrovirus enter this new cell? And if the answer is the latter - Why can't AIDS pateints, that takes drugs to kill HIV, get healthy? is it because the drugs are not able to destroy all of the HIV outside the cells, or because of another reason?

    I would be glad if, after a scientific explanation (if you would like that), you would be able to explain it for me as well as for other people here in a simple language, even if it does not comes out as accurate as it comes out in the scientific language. For me, especially because I come from Israel and English is not my first langauge, but most of all because I'm not a scientist, It's sometimes hard to understand the scientific explanations.

    Thanks in advance!
  7. George

    George Guest

    I'll give it a shot

    Right Lj-001 is a good candidate to stop XMRV from getting into cells that it's not already in. It's only a candidate right now because they haven't done extensive animal models (a couple of years) and then human models ( a couple of years there) and then it could be considered for treatment of disease's. But you are correct that it would do nothing for XMRV already in the persons body.

    Right now there are companies that are testing drugs to kill XMRV at diffrent stages of it's life cycle. For instance before it enters a cell, when it attaches to a cell, when it enters a cell, and when it's actually making copies inside of cell. There are all kinds of cool names for those processes but, for now, just know that they are testing current AIDS drugs and have found AZT to work. (It's a really nasty drug though) And they are testing many drugs that didn't work for HIV to see if some of them will work on XMRV. They are doing all of these tests in test tubes (in vitro) then they will try to infect and cure animals (in vivo)

    Yes in the case of XMRV you have the virus in your cell, when your cell makes a new cell it makes the new cell with the virus inside of it as well. Now you have two cells that can make more XMRV virus. But XMRV appears to be a very laid back virus. It makes only one or two copies of itself and then just hangs out in your cells. It mostly messes up your system by creating proteins that interfere with normal body processes. Which process and how hasn't been figured out yet.

    The answer to the AIDS question is that HIV makes 20 to 50 copies of itself in every cell. It's a very aggressive virus! When it makes all those copies it makes mistakes in the copies, meaning that there are differences in many of the copies from the original. This is called Quasi species. So a drug that works on one Quasi species won't necessarily work on another Quasi species. It's like the cold or flu bug. The reason why they can't cure the common cold is because it makes so many thousands of copies and therefore there are hundreds of mistakes and that means hundreds of quasi species. So you could cure one virus type but not another.

    Hope that helps!
  8. omerbasket

    omerbasket Senior Member

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    It does help and it's very clear. What I didn't understand yet is: If HIV infect the human cells, and when the cell is dividing HIV is already in the new cell, and if you can't kill the virus inside the cell (if I understood you correctly), than, how does a pateint who have AIDS for some time gets better with drugs? I mean, Let's say a patient feel very bad. He goes to his doctor and after a while they diagnose him with AIDS. They then find out that every cell in his body has, let's say, 50 HIV copies. also, HIV is making new copies, in many ways. But currently he just suffers from those 50-per-cell copies. Than they give him drugs, that, let's assume, doesn't let the HIV to make even one more copy. The patient gets better, doesn't he? But here is my question: When he felt very bad, and had 50 copies of HIV in every which cell of his body (I'm not saying that in reality every cell in the body has the number of HIV copies as another cell have, but to understand the principale let's say it is so), he was suffering because of this 50 copies of HIV per cell, wasn't he? I mean, he wasn't suffering from the HIV copies that were'nt produce yet. Than they gave him a drug and he felt better. It's not that his condition just stopped deteriorating. He got much better. But we say that we can't kill the HIV that is already in the cells, no? So why does the patient feel better? does these copies die when time goes by (without a connection to the medication, that is just making it impossible, in my example I mean, for the virus to make new copies)? And if so - than why doesn't AIDS patients get cured? Is it because there are still no drugs out there that would totally prevent a HIV from making copies? And if so, do you see a possibility that there will be drugs that can do so and therefore cure AIDS patients in the future (not saying that there will be - just asking if there is any known reason for it to be impossible)?

    Thanks, and once again, your answers, as well as answers of other scientists here, are of a huge, huge help for me and I think that also for the rest of the members here.
  9. Hope123

    Hope123 Senior Member

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    Yes, I'm glad we have Dr. R(acaniello) writing his blog; it's a great having an academic virologist help interpret things in clear language.

    Re: HIV. I read a recent article on the development of HIV drugs - last year was the 25th anniversary I believe of the first drug out for HIV, AZT. The authors writing the article were the people that found that AZT, originally developed as a cancer drug, affected HIV. They wrote it was a bet on their part that inhibiting replication would help greatly. This was a surprising assumption at the time. Many other scientists doubted them citing that retroviruses integrated into cell DNA and inhibition of replication would not help.

    These are good questions. Aside from cell division, cell death and production of new cells from stem cells also plays into this. Cells do not divide endlessly, unless they are cancer cells; at some point, they die and their DNA gets chomped up by the processes in our body that do janitorial duties. There was a thread on this forum which talked about the time it takes various immune cells to die. Range was weeks (NK cells) to more than a year (B-cells) to some lifetime T-cell types.

    Entirely new cells may not be infected. Also, which cells are affected may also make a difference. In HIV, where CD4 cells are targeted especially, HIV drugs may suppress infections of "clean" CD4 cells enough that they are able then to help defend against HIV and other infections. This is of course a dynamic process (dying, dividing, production of new cells, balance of clean CD4 cells, etc.) so that depending on the balance of these processes, the person may be more or less sick. HIV can hide out in some cells and not replicate (called latent infections) a lot; when this HIV does replicate, it causes havoc. We have no way to treat latent HIV infections currently so that is why HIV patients have to keep taking HIV drugs.

    Also, I believe HIV patients feel bad (and this is very simplistic) from 1) opportunistic infections and 2) the immune system reacting to virus in the system. This is a guess on my part but latent virus perhaps doesn't cause the same strong immune system reaction as active virus in the bloodstream.
    (It's been a while since I've studied basic bio so please correct me on some of this if needed.)

    From reading the article, the lesson I drew from it is that skepticism/ theory is important but we also need to be open-minded. Maybe XMRV doesn't make too many copies but we (I mean not solely us but researchers in general) should be careful about jumping to conclusions that stopping replication won't help. Perhaps it's a stong enough virus that even low copy numbers are enough to cause us lots of trouble.
  10. George

    George Guest

    Let me see

    Let say that you have an HIV positive person.

    This person has 1000 cells that are infected, each cell is busy making copies of itself. If that person doesn't have any drugs then the "copies" burst out of the cell and go infect other cells. Over and over again until all of the possible cells that the virus can infect are infected.

    Now if the person takes a drug that is designed to keep the HIV from entering the cell that's called a Fusion Inhibitor. It doesn't kill the virus but binds with it to keep it from ever entering another cell. So in effect the HIV virus dies off and just gets washed out of the body via urine

    If iHIV get's into the cell then you have to take a drug that keeps the HIV from inserting itself into the DNA and later making copies of itself this is called a NRTI or NUKE and stands for Nucleotide Reverse Transcriptase Inhibitors.

    There are also drugs for when HIV tries to make copies and when it tries to leave the cell and go infect other cells.

    This is a link if you want to look at all 5 parts of the life cycle. HIV Life Cycle and Drug Therapy

    So if a person is taking all these drugs why don't all of the viruses die and the person be cured? For the same reason we can't cure the common cold or flu. Because these viruses mutate so quickly that they are brand new viruses in a matter of weeks or months.

    Think about the flu, every year a new flu comes around. It's still a flu bug (called a Para Virus) but it's mutated so that you have no antibodies to it, which means your body has to fight it all over again just like it did with the flu virus from last year and the year before that. Same with a cold virus (called a Rhino Virus). The thing is that a cold or the flu won't kill you in a matter of years from the time you get it. HIV replicates so fast and so heavy that the body is overwhelmed in a very short time. HIV itself doesn't kill the person but other bugs can get in and because the body has no defense the body eventually dies.

    Because the HIV mutates so fast it also becomes immune to the drug therapies. So the best Doctors can do right now is to offer a different set of drugs and then change that set every few months to keep the HIV from creating mutations that are drug resistant. They are already finding strains that are resistant to current drugs.

    I hope this helped but if you are really interested you will want to look it up on the internet. There are a lot better explanations than what I can do!
  11. omerbasket

    omerbasket Senior Member

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    I just want to ask theses questions: 1)As I understood form you two (an interesting play on words, isn't it?), Hope123 and Geroge, It's possible that if we completely keep the retrovirus (and it's mutations) from replicating outside of the cells (and because the cells die sometimes and they are replaced by stem cells which doesn't have, at least in the beginning, the retrovirus DNA in them), the person would become completely healthy?
    Because it has been said that XMRV is a simple retrovirus which doen't replicate much and doen't mutant much (at least for now...), right? So, perhaps it would be possible for a person with a disease caused by XMRV to get completely hilled, if there would be a drug that would kill XMRV outside the cells?

    2) And this also bring us back to the topic of this thread: If there really as such a compund, which acts like broad spectum antibiotics, so perhaps it would be able to kill not only the "classic" HIV or XMRV, but also it's mutations. I mean, it kills tens of kind of viruses. So why wouldn't it kill mutations of HIV or XMRV.
  12. cfs since 1998

    cfs since 1998 *****

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  13. parvofighter

    parvofighter Senior Member

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    I want it all!

    First: I'm switching to Diesel! :Retro smile: And now for happy hour: I want a cocktail... something like this, and not necessarily in this order:

    • Kill the circulating XMRV viruses with envelope-specific drugs such as: LJ-OO1; and/or with HIV antiretrovirals being currently re-studied for XMRV.
    • Remember this: http://www.wpinstitute.org/xmrv/index.html The WPI's "Current Working Hypothesis": "The current working hypothesis is that XMRV infection of B, T, NK and other cells of the innate immune response causes the chronic inflammation and immune deficiency resulting in an inability to mount an effective immune response to opportunistic infections."
    • B-cell depletion therapy: Rituximab, Bavituximab, etc - get rid of the XMRV-infected B-cells. (Remember all that buzz about ME/CFS patients with unrelated cancers, getting chemo, and it ends up dramatically helping their ME/CFS symptoms.
    • Targeted chemo to eradicate viral reservoirs: I commented on this earlier - see http://forums.aboutmecfs.org/showth...ANTI-RETROVIRAL-Drugs-Work&highlight=montreal , with the specific article cited: Treatment of HIV 'sanctuary' cells creates path for possible cure: http://www.montrealgazette.com/story...20793&sponsor=
    • Cheney's autologous stem cell therapy. New mitochondria, new B-cells??
    • Targeted antivirals etc. to address opportunistic infections. Eg. IVIg for parvo; Valganciclovir for EBV, etc. Depends on your unique blend.
    • Alternatives & nutriceuticals etc: Low-dose naltrexone, Vit D, sublingual B12, curcumin, gluten-free diet, etc. etc.
    • Oh, and of course immune modulators - again this isn't in chronological order.
    And something to pull me out of this crash :ashamed:
  14. guest

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    I have a little question. Let's suppose a person with HIV has all its cells infected. Now he takes LJ-001 and blocks entry for HIV viruses. My question is: As soon as the virus is present in every cell does it ever need to get out of one cell and into another again? Hope123 explained it pretty good but I'm still a little confused.
  15. guest

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    Everything is pointing towards a viral infection. I'm waiting for the first positive replication study so science can proceed from there.
  16. Hope123

    Hope123 Senior Member

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    The thing about science is the more you know, the more you realize how little we know! So, I'll try to answer but my basic science days are far behind me and I don't keep up with the literature anymore. I think Dr. R. takes questions so it might be worth it to run some questions by him.

    1) We can't assume this. I bet there are people with HIV out there who have no virus in their bloodstream as detected by current methods and are still pretty sick. They might not be common but they're probably out there. As has been mentioned, non-replicating XMRV still might have effects on us, whether through proteins or through the immune system, etc.

    2) Our immune systems are in a constant struggle with attacking bacteria and viruses to maintain our health. Mutations happen spontaneosly and if a mutation confers a sruvival advantage to a virus or bacteria, it will flourish while others of its type die. In this case, the antiviral is the evolutionary pressure favoring bugs with mutations that help it survive against the antiviral. The history of antibiotic development is all about us staying one step of the game ahead of bacteria.

    Toxicity of the drug is what concerns me. As pointed out earlier, it still might affect our cell membranes, just not as much. But the real question of how much has to be answered by more animal studies and later on, human studies. This drug reminds me of polymixins:

    http://en.wikipedia.org/wiki/Polymixin
    I don't think anyone understands enough about the triggers for viral replication in XMRV yet, nor for HIV, although we know more about HIV than XMRV.
  17. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Clay, Alabama
    Well, I am thinking that CFS is the immune system abnormal loop that has XMRV as an original cause. But, the loop might continue without XMRV replication, in my theory. Now this might sound less than hopeful. But in fact, I think that without further damage from continued XMRV infecting new cells, the loop can gradually be broken. In fact, most people with CFs do see some improvement over a few years. So even without blocking XMRV replication, the process can be undone. But I don't think you can test level of XMRV and relate that to level of illness. The illness is the rest of the stuff reacting within itself after the damage of XMRV starts it. Now, this is just my theory. This might explain why there can be very sick people with CFS and yet, you can't find it in assays. It is because the illness is not directly connected to XMRV, but to the damage caused by XMRV, even if the XMRV has gone back into dormancy.

    I think the thing is that the factors that trigger XMRV are things that happen to us on a regular basis, such as cortisol release, progesterone spikes, etc. So the instigator fo the loop appears again and again, but disappears again and again. This might explain our "good days / bad days."

    Seems the low replication may work in our favor. As has been said, if replication is halted even more than is natural for the virus, through this drug, then the immune system and HPA may get enough relief to recover more quickly. But, it may also means we need more than just something to stop the virus.

    As has been said, this might explain why HIV kills but CFS is chronic, killing only a few (that we know of, unless it causes lymphoma, prostate cancer, etc. which is actually very possible in my mind.)

    When my mother had breast cancer at 49, I was with her at her first oncologist visit. My, I will never forget that day. We went from healthy mom to mom has breast cancer and it is removed within a week. By second week, we were in oncologist office. My mother was actually secretly thinking she might forgo the chemo and radiation. But that day in the oncologist's office was bad, bad news. We had already had disappointments. "We see the lump, but don't worry, 80% are benign." Well, hers wasn't. Then the surgery, "Don't worry, most of the time it isn't in the lymph nodes." But hers was. "Oh, don't worry, most are not in many lymph nodes, meaning only six weeks of chemo." Well, hers was over the figure, it was in more than four.

    So the oncologist then had other bad news.... it isn't estrogen sensitive. That means we can't use estrogen depletion to help kill it, we lost one of our weapons in your case.

    And by the way, she was given 50% chance of survival with nine months of chemo and six weeks of radiation. (side note, she survived and has not seen recurrence in over ten years.)

    My point is this, we need every weapon we can throw at our multi-system illness. If we can get this virus from four different angles, boost our immune system, hinder it by controlling progesterone and cortisol, get sleep for HPA health, then maybe we can lick this thing. I am very hopeful that there are multiple weapons available to us with this particular virus. And we may not need multiple antiretroviral drugs as in the case of HIV, because it doesn't replicate often. We just need to make it so it doesn't replicate at all, and maybe our immune system will heal itself.

    By the way, when the virus has infected all the cells it can, then the viral load (loose in the blood) may go down because not enough new cells to infect, so replication stops. But it is in most of the cells doing damage. Again, another explanation of why it may not be easy to find.

    Tina
  18. guest

    guest Guest

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    K, we will see. Thanks a lot anyways :)
  19. omerbasket

    omerbasket Senior Member

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    Thanks a lot :Retro smile:
  20. Overstressed

    Overstressed Senior Member

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    Hi,

    I think it's interesting to read the discovery of a smart German Scientist, Baur, and his finding on the Nef protein. If I'm correct, it explains how HIV kills so many CD4-cells(and cause AIDS), because it was known that it only infects a subset of these, same cells.

    Once inside the cells, HIV forces the cell to produce Nef, which makes the immune system fight against itself, by killing CD4-cells, although the dying cells are not directly infected by HIV. HIV does this through an autoimmune reaction, so the link, retrovirus and autoimmune is also set...

    OS.

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