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explain this? "BIOCHEMICAL, STRUCTURAL, INHIBITION STUDIES OF XMRV REVERSE TRANSCRIPT

Discussion in 'XMRV Research and Replication Studies' started by RivkaRivka, Nov 22, 2010.

  1. RivkaRivka

    RivkaRivka Senior Member

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    Can anyone explain to me what this paper means??? - Best, Rivka
    _______



    http://antiviralresistance.org/abstr...ster5_2010.pdf

    POSTER 5

    BIOCHEMICAL, STRUCTURAL, AND INHIBITION STUDIES OF XMRV REVERSE TRANSCRIPTASE

    Tanya Ndognwe1, Karen Kirby1, Bruno Marchand1, Adeyemi Adedeji1,
    Eleftherios Michailidis1, Yee-Tsuei Ong1, Atsuko Hachiya1, Emily
    Ryan1, Shun-Lu Liu1, Angela Whatley1, Donald H. Burke1, Sanath Kumar1,
    Marc Johnson1, Ei-Ichi Kodama2, Krista A. Delviks-Frankenberry3, Vinay
    K. Pathak3, Hiroaki Mitsuya4, Michael A. Parniak5, Kamal Singh1, and
    Stefan G. Sarafianos1

    1Department of Molecular Microbiology & Immunology, University of
    Missouri School of Medicine, Columbia, MO; 2Division of Emerging
    Infectious Diseases, Tohoku University School of Medicine, Sendai,
    Japan; 3HIV Drug Resistance Program, National Cancer Institute,
    Frederick, MD; 4Department of Internal Medicine, Kumamoto University
    School of Medicine, Kumamoto, Japan & Experimental Retrovirology
    Section, HIV/AIDS Malignancy Branch, NIH, Bethesda, MD; 5Department of
    Molecular Genetics & Biochemistry, University of Pittsburgh School of
    Medicine, Pittsburgh, PA

    The Xenotropic Murine Leukemia Virus-Related Virus (XMRV) was
    originally identified in biological samples from familial prostate
    cancer patients and was more recently reported in patients with
    chronic fatigue syndrome (CFS). Although other studies have failed to
    detect XMRV in CFS or prostate cancer patients, given the potential
    importance of this virus for human disease we initiated studies on its
    replication mechanism and susceptibility to inhibitors. We used
    biochemical, biophysical, virological, and structural methods to
    characterize the DNA polymerase and RNase H functions of XMRV reverse
    transcriptase (RT). We compared the properties of XMRV RT, XMRV RNase
    H, Moloney Murine Leukemia Virus (MuLV) RT, and HIV RT. Using steady
    state and pre-steady state kinetics we demonstrated that XMRV RT is
    the slowest and least efficient of the three enzymes in synthesizing
    DNA or cleaving RNA/DNA. Similarly, its ability to unblock
    chain-terminated primers using PPi or ATP are much lower compared to
    HIV RT. Its reduced polymerase and RNAse H activity is due in part to
    a lower affinity for nucleic acid, as judged by gel-shift assays and
    confirmed by surface plasmon resonance experiments, which revealed
    that the deficiency in DNA binding is due to a high dissociation rate.
    Trap experiments showed that XMRV RT has very low processivity
    compared to HIV RT. Transient kinetics of mismatch incorporations
    revealed that XMRV RT has higher fidelity than MuLV and HIV RTs.
    Nonetheless, XMRV and MuLV appear to have comparable fidelities in
    cell-based assays. The polymerase function of XMRV RT is susceptible
    to antiretrovirals from several classes, but not to NNRTIs. XMRV RT is
    inhibited efficiently by AZT-TP, PMEADP, d4T-TP, PMPA-DP, and by a
    nucleic acid aptamer. Two potent NRTIs that block XMRV RT efficiently
    by a different mechanism also have potent antiviral activity in
    pseudotype-based and replication competent virus-based assays. We have
    also identified compounds that efficiently block the RNase H activity
    of XMRV RT and of active XMRV RNase H fragments. Finally, we have
    solved the crystal structure of XMRV RNase H at high resolution (1.5
    ), which will facilitate the design of new and more potent XMRV
    inhibitors.
     
  2. urbantravels

    urbantravels disjecta membra

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    Los Angeles, CA
    It's technical stuff about the way reverse transcriptase (the enzyme that allows the RNA in a retrovirus to "copy" itself into DNA) works in XMRV. Blocking the action of reverse transcriptase is one of the ways that HIV drug "cocktails" work to suppress replication of the virus.

    I'm not knowledgeable enough to say for sure, but it doesn't appear that the information in this study would cast any light on either detection or pathogenesis - it's just information that might ultimately help identify or develop drugs to treat XMRV.
     
  3. RivkaRivka

    RivkaRivka Senior Member

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    very helpful. thanx!
     
  4. eric_s

    eric_s Senior Member

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    Switzerland/Spain (Valencia)

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