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Journal of Virology on XMRV, AZT, tenofovir, and raltegravir

Discussion in 'XMRV Research and Replication Studies' started by subtr4ct, Mar 26, 2010.

  1. subtr4ct

    subtr4ct Senior Member

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    Related research entitled "Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins 2 and Antiviral Drugs" is forthcoming in the Journal of Virology, and a preprint is available here.

    At the end of the abstract, they indicate that in addition to AZT, they find that XMRV is susceptible to tenofovir and raltegravir in vitro.

    Well, darn. I see when browsing from my phone (rather than from work) that this is behind a paywall. It can never hurt to PM me.
     
  2. subtr4ct

    subtr4ct Senior Member

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    Abstract of the new paper:

    Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs.

    Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu WS, Pathak VK.

    HIV Drug Resistance Program, National Cancer Institute at Frederick, Viral Mutation Section and Viral Recombination Section, Frederick, MD 21702, USA.

    Xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus, has been isolated from human prostate cancer tissue and from activated CD4(+) T cells and B cells of patients with chronic fatigue syndrome, suggesting an association between XMRV infection and these two diseases. Since APOBEC3G (A3G) and APOBEC3F (A3F), which are potent inhibitors of the murine leukemia virus and Vif-deficient human immunodeficiency virus type 1 (HIV-1), are expressed in human CD4(+) T cells and B cells, we sought to determine how XMRV evades suppression of replication by APOBEC3 proteins. We found that expression of A3G, A3F, or murine A3 in virus producing cells resulted in their virion incorporation, inhibition of XMRV replication, and G-to-A hypermutation of the viral DNA with all three APOBEC3 proteins. Quantitation of A3G and A3F mRNA indicated that compared to human T-cell lines CEM and H9, prostate cell lines LNCaP, and DU145 exhibited 50% lower A3F mRNA levels, whereas A3G expression in 22Rv1, LNCaP and DU145 cells was nearly undetectable. A low frequency of XMRV proviral genomes in LNCaP and DU145 cells were hypermutated with mutation patterns consistent with A3F activity. XMRV proviral genomes were extensively hypermutated upon replication in A3G/A3F-positive T cells (CEM and H9) but not in A3G/A3F-negative cells (CEM-SS). We also observed that XMRV replication was susceptible to nucleoside reverse transcriptase (RT) inhibitors AZT and tenofovir, and integrase inhibitor, raltegravir. In summary, the establishment of XMRV infection in patients may be dependent on infection of A3G/A3F-deficient cells and that cells expressing low levels of A3G/A3F, such as prostate cancer cells, may be ideal producers of infectious XMRV. Furthermore, anti-HIV-1 drugs AZT, tenofovir, and raltegravir may be useful for treatment of XMRV infection.
     
  3. _Kim_

    _Kim_ Guest

    I posted the full text to the Library. Subtr4ct, you will need to PM one of the Administrators to request Library access (or send me a PM with your email address and I will send it to you).
     
  4. subtr4ct

    subtr4ct Senior Member

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    More info on various antiretrovirals effectiveness against XMRV in vitro

    They not only found two new drugs that were effective agains XMRV in vitro, they also found several things that were not effective at concentrations used against HIV or not effective at all:

     
  5. cfs since 1998

    cfs since 1998

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    This is dynamite!

    By the way can we split the thread? I think the new drug research deserves its own thread.
     
  6. subtr4ct

    subtr4ct Senior Member

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    Yeah -- I was surprised no one was noticing this. I probably should have put it somewhere else. Seems like big news to me
     
  7. subtr4ct

    subtr4ct Senior Member

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    According to this, raltegravir is much, much safer than AZT. And may be less likely to result in resistance. Sound very promising.
     
  8. Hope123

    Hope123 Senior Member

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    Great stuff, everyone! That's actually a good picture - he looks warm and approachable.
     
  9. parvofighter

    parvofighter Senior Member

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    More goodies on treatment of XMRV

    Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs. J Virol. 2010 Mar 24. [Epub ahead of print]
    From: http://www.ncbi.nlm.nih.gov/pubmed/20335265
    Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu WS, Pathak VK.
    HIV Drug Resistance Program, National Cancer Institute at Frederick, Viral Mutation Section and Viral Recombination Section, Frederick, MD 21702, USA.
    Xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus, has been isolated from human prostate cancer tissue and from activated CD4(+) T cells and B cells of patients with chronic fatigue syndrome, suggesting an association between XMRV infection and these two diseases. Since APOBEC3G (A3G) and APOBEC3F (A3F), which are potent inhibitors of the murine leukemia virus and Vif-deficient human immunodeficiency virus type 1 (HIV-1), are expressed in human CD4(+) T cells and B cells, we sought to determine how XMRV evades suppression of replication by APOBEC3 proteins. We found that expression of A3G, A3F, or murine A3 in virus producing cells resulted in their virion incorporation, inhibition of XMRV replication, and G-to-A hypermutation of the viral DNA with all three APOBEC3 proteins. Quantitation of A3G and A3F mRNA indicated that compared to human T-cell lines CEM and H9, prostate cell lines LNCaP, and DU145 exhibited 50% lower A3F mRNA levels, whereas A3G expression in 22Rv1, LNCaP and DU145 cells was nearly undetectable. A low frequency of XMRV proviral genomes in LNCaP and DU145 cells were hypermutated with mutation patterns consistent with A3F activity. XMRV proviral genomes were extensively hypermutated upon replication in A3G/A3F-positive T cells (CEM and H9) but not in A3G/A3F-negative cells (CEM-SS). We also observed that XMRV replication was susceptible to nucleoside reverse transcriptase (RT) inhibitors AZT and tenofovir, and integrase inhibitor, raltegravir. In summary, the establishment of XMRV infection in patients may be dependent on infection of A3G/A3F-deficient cells and that cells expressing low levels of A3G/A3F, such as prostate cancer cells, may be ideal producers of infectious XMRV. Furthermore, anti-HIV-1 drugs AZT, tenofovir, and raltegravir may be useful for treatment of XMRV infection.

    Folks, tenofovir is the new kid on the block, isn't it?Not quite up to analysis today - any takers?
     
  10. cfs since 1998

    cfs since 1998

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  11. parvofighter

    parvofighter Senior Member

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    Oops!

    Oops - sorry bout that! George - don't bite me. Down George. Baaaack.:tongue:
     
  12. cfs since 1998

    cfs since 1998

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    You don't have to apoligize, it really need(s/ed) its own thread. So I'm not sure if we should continue discussing it here or there :worried:
     
  13. George

    George Guest

    Hey Parvo you big awesome dog, I'll share my bones with you anytime. (big grins). How about we get an admin to merge the threads??
     
  14. julius

    julius Watchoo lookin' at?

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  15. Kati

    Kati Patient in training

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    Julius, price may not be as high here in Canada, and pharmacare could possibly cover. Sometimes the companies gives the drug as compassionate program type of thing.
     
  16. George

    George Guest

    Tenofovir disoproxil fumarate is a prodrug form of Tenofovir. Tenofovir is also available in a fixed-dose combination with emtricitabine in a product with the brand name Truvada for once-a-day dosing. (Emtricitabine is marketed as a single-compound product called Emtriva, also by Gilead.) Atripla, a fixed-dose triple combination of tenofovir, emtricitabine and efavirenz, was approved by the FDA on 12 July 2006 and is now available, providing a single daily dose for the treatment of HIV.
     
  17. parvofighter

    parvofighter Senior Member

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    YES George - combine the threads! I want that bone.
     
  18. fds66

    fds66 Senior Member

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    Well, I've tried to read through the full paper and although I've had to skim the most technical parts there are a few things that jumped out at me that I wondered if other people had noticed. I am in no way an expert in this and I may have got this completely wrong and I hope someone more knowledgeable may explain this better.

    They examined how susceptible XMRV was to two build in defence mechanisms in the body - A3G and A3F. They found that it did affect the replication of XMRV and so XMRV grew better in cells without those mechanisms like LNCaP (prostate cancer cell line?) - the cell line that has been found to be best to grow XMRV. Could that be the reason why this cell line is so good an environment for replicating XMRV?

    Also they found that the some cells like T cells and B cells do use this defense mechanism and can reduce the replication of XMRV. I got a little confused in this section because there was discussion of many different cell types that I'm not familiar with. In the conclusions though it say that some XMRV may still remain in these cells at a low level. Could this be why XMRV is harder to find in the blood?

    They discovered that one of the ways the A3G and A3F reduce the replication is introducing mutations into the XMRV and they could see these mutations where the XMRV had been in contact with A3G and A3F.

    Could these mutations that are introduced affect the type of testing where you look for specific sequences? I don't know if that is possible or if they affect the relevant part of the sequence.

    From the conclusions

    They also tested a variety of HIV drugs and found

    Was a very technical paper and it was difficult to even understand the conclusions properly without a background in this area.

    Hope that my inexpert comments may help to start a discussion.
     
  19. Gerwyn

    Gerwyn Guest

    tenovir has been around since 2001 it competes with neucleotide bases on the reverse transcriptase active site and works like putting a spanner in a coveyor belt bringing the assembly process of making cDNA to a grinding halt.
     
  20. cfs since 1998

    cfs since 1998

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    How do the safety of tenofovir and raltegravir compare? Since it seems they needed at least twice as much tenofovir but only less than half as much raltegravir to inhibit XMRV compared to HIV.
     

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