A Little Poisoning Along the Road to ME/CFS
Looking at my symptoms, many of which are far less these days and some are gone, it would be easy to figure that I'd just been dealing with some heavy-duty menopausal issues.
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new study on arv in vitro

Discussion in 'XMRV Testing, Treatment and Transmission' started by leaves, Oct 6, 2010.

  1. leaves

    leaves Senior Member

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    http://www.medscape.com/viewarticle/729233_2

    havent seen this before right?

    Background

    The genus gammaretroviridae includes several well-characterized exogenous retroviruses that cause leukemia, lymphoma and other diseases in their natural hosts.[1] Although gammaretroviruses have been isolated from several vertebrate species, until recently, the only evidence that these agents could infect humans was the strong sequence similarity between certain human endogenous retroviruses and gammaretroviruses from other mammalian species.[2] In 2006, Urisman and colleagues reported the discovery of novel gammaretroviral cDNA sequences in tumor samples from patients with prostate cancer.[3] Full-length viral clones derived from the patient tissues were shown to be genetically similar to xenotropic strains of murine leukemia virus (MLV), and thus, the novel retrovirus was named xenotropic MLV-related virus (XMRV).

    Subsequent studies have provided compelling evidence that XMRV is indeed the first known example of an exogenous human gammaretrovirus. XMRV sequences have been identified in tumor samples from three additional cohorts of prostate cancer patients,[4–6] in a prostate carcinoma cell line,[7] and in secretions expressed from cancerous prostate tissues.[8] Virus produced from a full-length XMRV molecular clone can infect primary prostate cells in culture, as well as several immortalized cell lines,[7–12] and gammaretrovirus-like particles have been identified in XMRV-infected cultures by electron microscopy.[5,7] Although XMRV lacks direct transforming activity, foci of transformed cells appear at low frequencies in XMRV-infected fibroblast cultures, suggesting that the virus is capable of promoting carcinogenesis via insertional activation of cellular oncogenes.[13] Importantly, the chromosomal locations of XMRV proviruses have been mapped in tissue samples from 9 different patients with prostate cancer, confirming that XMRV can integrate into the human genome in vivo.[11,14]

    Following the discovery of XMRV in prostate tumor tissues, a PCR-based survey identified XMRV DNA in peripheral blood mononuclear cells (PBMC) from 68 of 101 chronic fatigue syndrome (CFS) patients living in the United States, as well as 8 of 218 healthy controls.[15] Remarkably, co-culture experiments revealed the presence of infectious XMRV in activated PBMC and in cell-free plasma samples from PCR-positive CFS patients, suggesting that these individuals harbor significant levels of replication-competent XMRV in the periphery. Although other studies of CFS and prostate cancer patients living outside the United States have failed to detect XMRV,[16–20] data showing that the virus can infect human cells in vitro [7–12] and in vivo [11,14] provide a solid rationale for identifying antiviral inhibitors that block XMRV replication.

    A growing body of evidence suggests that XMRV is intrinsically resistant to many of the drugs used to treat HIV-1 infection, but is sensitive to a small subset of antiretroviral inhibitors. In an initial analysis of XMRV drug susceptibility, treatment of immortalized prostate cells with 30 nM AZT inhibited XMRV infection by a factor of 25-fold; equivalent concentrations of other antiretroviral drugs had no effect on XMRV infection.[21] A subsequent study in cultured cells found that XMRV and HIV-1 exhibit comparable sensitivities to AZT, tenofovir disoproxil fumarate (TDF), and raltegravir suggesting that these drugs are relatively potent inhibitors of XMRV replication.[22] Finally, Singh et al. reported that AZT, TDF, raltegravir and the integrase inhibitor L-870812 inhibit XMRV infection at nanomolar concentrations in culture.[23] Although drug susceptibility data for HIV-1 were also presented, direct comparisons between XMRV and HIV-1 could not be made due to the differing cell types used to assay these viruses (i.e., immortalized breast and prostate cancer cells for XMRV versus primary blood lymphocytes for HIV-1).[23]

    In the present study, we examined the ability of specific reverse transcriptase (RT), protease, and integrase inhibitors to block XMRV infection in culture by directly comparing the antiretroviral drug susceptibilities of XMRV and HIV-1 in the same host cell type. Our use of the same target cells for both viruses was particularly critical for assessing nucleoside RT inhibitor (NRTI) susceptibility, since the antiviral activity of these drugs varies widely in different host cell environments.[23,24] We also used conditions that restricted viral replication to a single cycle of infection to ensure that our drug susceptibility measurements were not influenced by differences in the relative replication rates of HIV-1 and XMRV. As in previous reports, we found that XMRV is intrinsically resistant to nevirapine, efavirenz, foscarnet, and all FDA-approved inhibitors of HIV-1 protease. However, our data also show that in addition to AZT and tenofovir, XMRV and HIV-1 are comparably sensitive to other structurally-related NRTIs. These findings reveal a distinct pattern of NRTI sensitivity in XMRV that correlates with the structure of the pseudosugar moiety. We also demonstrate that the integrase inhibitor elvitegravir suppresses XMRV infection with an EC50 similar to that of AZT, whereas raltegravir is the most potent anti-XMRV agent of all the inhibitors tested. These data suggest that the inhibitor-binding surfaces of HIV-1 and XMRV integrase share similar topologies despite numerous differences in their respective amino acid sequences. Collectively, our study reveals important features of the inhibitor specificities of XMRV RT and integrase and expands the number of antiretroviral drugs that are active against XMRV in culture.
     
  2. leaves

    leaves Senior Member

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    could a mod change the title to ; in vitro...thanks!
     
  3. August59

    August59 Daughters High School Graduation

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    Upstate SC, USA
    I think "urbantravels" just posted the abstract for this on another thread. It was originally posted on 8/31/10 per "mjoey's" reply to that post. That is if it is the same article!?!?!
     
  4. leaves

    leaves Senior Member

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    OOps I see...
     
  5. urbantravels

    urbantravels disjecta membra

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    WPI just posted it on their Facebook page today as if it were new info. That's where I got it from. Is it new, or not?
     
  6. leaves

    leaves Senior Member

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    Its new on medscape but was published earlier in retrovirology I believe
     
  7. urbantravels

    urbantravels disjecta membra

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    The problem with Medscape is if you cut and paste the URL, then when others try to click on it it leads to a medscape sign-in page rather than the article.
     
  8. August59

    August59 Daughters High School Graduation

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    Upstate SC, USA
    The only way I assumed it was the same was by the number of the article. For the reason you mentioned above about the login page. It sure grabbed my attention really quick though because I had missed it earlier, thanks!
     
  9. Daffodil

    Daffodil Senior Member

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    i saw this one a while ago
     
  10. Hope123

    Hope123 Senior Member

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    Article published at end of August. Haven't read through it yet but not sure if it adds anything new.

    Retrovirology is open access for full-text:

    http://www.retrovirology.com/content/7/1/70

    I have full access to Medscape so if future full-text needed from that site, I can try to obtain a copy if I am PM'd.
     
  11. leaves

    leaves Senior Member

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    I know and I asked for this thread to be removed, but I guess mods are busy
     

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