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XMRV: usage of receptors and potential co-receptors

Discussion in 'XMRV Research and Replication Studies' started by Ecoclimber, Jun 14, 2012.

  1. Ecoclimber

    Ecoclimber Senior Member


    Conclusions not supported by the data

    A Dusty Miller (2012-06-13 10:12) Fred Hutchinson Cancer Research Center [​IMG]
    This report claims two major conclusions (first and last paragraphs of the Abstract):

    1. "Although XMRV is thought to use XPR1 for cell entry, it infects A549 cells that do not express XPR1, suggesting usage of other receptors or co-receptors."

    2. "XMRV replication was observed in GHOST cells that express CD4 and each of the chemokine receptors ranging from CCR1- CCR8 and BOB suggesting that infectivity in hematopoietic cells could be mediated by use of these receptors."

    Neither conclusion is supported by the data.

    First, some background. The Xenotropic and Polytropic retrovirus Receptor (XPR1) was discovered independently by three research groups in 1999 [1-3]. These groups screened cDNA expression libraries from different sources for production of proteins that could mediate xenotropic [1,2] or polytropic [3] retrovirus entry into cells that were normally nonpermissive for virus infection. The fact that they all came up with the same receptor provides evidence that there is only a single receptor for these viruses. Additional support for a single virus receptor comes from a subsequent study using human/hamster radiation hybrid cell lines to map genes in the human genome that could act as receptors for xenotropic retroviruses, which again found only one gene, XPR1 [4]. Furthermore, XPR1 mRNA was found to be expressed in all human tissues tested [1,2], thus, there is no need to postulate additional receptors to explain the ability of xenotropic and polytropic retroviruses, including XMRV, to infect many cell types.

    So, what about the current authors' first claim that XMRV infects A549 cells, but they don't express XPR1, suggesting XMRV can enter cells by using other receptors? They do present data that XMRV can infect A549 cells, but they do not provide any data showing that the cells do not express XPR1. Nor do they provide a literature reference for their statement, repeated multiple times, that A549 cells lack XPR1. A quick Google search reveals a gene expression atlas report ( that shows XPR1 is indeed expressed in A549 cells. Both gene expression studies listed found XPR1 RNA expression in A549 cells, with one showing higher than average levels and the other showing lower than average levels. Thus, in the absence of data to the contrary, A549 cells do indeed express XPR1, and no additional receptors need be postulated.

    What about the authors' second claim that XMRV might use some of the same receptors as does HIV? While they show data that XMRV can replicate in GHOST cells that express CD4 and various chemokine receptors, they've left out the crucial control - cells not expressing these receptors! GHOST cells are derived from HOS human osteosarcoma cells, and a report from 1990 clearly shows that HOS cells are highly infectable by the prototypical NZB strain of xenotropic virus [5]. So, it is likely that the extra receptors in the GHOST cells have nothing to do with xenotropic retrovirus infection. In summary, none of the data presented support the authors' overall conclusion that receptors in addition to XPR1 can mediate XMRV entry.

    So what's going on here? I've reread this paper several times to see if I've missed something. Instead, I found additional mistakes such as mislabeling of the panels in the two data figures. Perhaps a few critical paragraphs were inadvertently left out? What about Dr. Xue Wang, Dr. Mingjie Zhang, Dr. Robin Biswas, and Dr. Chintamani D. Atreya, who are acknowledged for critical review of this article? And how did peer review miss such seemingly obvious problems with this report? Perhaps the authors will explain to me what I've missed.

    1. Tailor CS, Nouri A, Lee CG, Kozak C, Kabat D (1999) Cloning and characterization of a cell surface receptor for xenotropic and polytropic murine leukemia viruses. Proc Natl Acad Sci USA 96: 927-932.
    2. Battini JL, Rasko JE, Miller AD (1999) A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: possible role in G protein-coupled signal transduction. Proc Natl Acad Sci USA 96: 1385-1390.
    3. Yang YL, Guo L, Xu S, Holland CA, Kitamura T, et al. (1999) Receptors for polytropic and xenotropic mouse leukaemia viruses encoded by a single gene at Rmc1. Nat Genet 21: 216-219.
    4. Rasko JE, Battini JL, Kruglyak L, Cox DR, Miller AD (2000) Precise gene localization by phenotypic assay of radiation hybrid cells. Proc Natl Acad Sci USA 97: 7388-7392.
    5. Sommerfelt MA, Weiss RA (1990) Receptor interference groups of 20 retroviruses plating on human cells. Virology 176: 58-69.
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