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PLOS ONE  2012 

Cholesterol Depletion Inactivates XMRV and Leads to Viral Envelope Protein Release from Virions: Evidence for Role of Cholesterol in XMRV Infection

DOI: 10.1371/journal.pone.0048013

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Abstract:

Membrane cholesterol plays an important role in replication of HIV-1 and other retroviruses. Here, we report that the gammaretrovirus XMRV requires cholesterol and lipid rafts for infection and replication. We demonstrate that treatment of XMRV with a low concentration (10 mM) of 2-hydroxypropyl-β-cyclodextrin (2OHpβCD) partially depleted virion-associated cholesterol resulting in complete inactivation of the virus. This effect could not be reversed by adding cholesterol back to treated virions. Further analysis revealed that following cholesterol depletion, virus-associated Env protein was significantly reduced while the virions remained intact and retained core proteins. Increasing concentrations of 2OHpβCD (≥20 mM) resulted in loss of the majority of virion-associated cholesterol, causing disruption of membrane integrity and loss of internal Gag proteins and viral RNA. Depletion of cholesterol from XMRV-infected cells significantly reduced virus release, suggesting that cholesterol and intact lipid rafts are required for the budding process of XMRV. These results suggest that unlike glycoproteins of other retroviruses, the association of XMRV glycoprotein with virions is highly dependent on cholesterol and lipid rafts.

References

[1]  Nguyen DH, Hildreth JE (2000) Evidence for budding of human immunodeficiency virus type 1 selectively from glycolipid-enriched membrane lipid rafts. Journal of virology 74: 3264–3272.
[2]  Campbell SM, Crowe SM, Mak J (2001) Lipid rafts and HIV-1: from viral entry to assembly of progeny virions. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 22: 217–227.
[3]  Chazal N, Gerlier D (2003) Virus entry, assembly, budding, and membrane rafts. Microbiology and molecular biology reviews: MMBR 67: 226–237, table of contents.
[4]  Ono A, Freed EO (2005) Role of lipid rafts in virus replication. Advances in virus research 64: 311–358.
[5]  Grek M, Bartkowiak J, Sidorkiewicz M (2007) [Role of lipid rafts in hepatitis C virus life cycle]. Postepy biochemii 53: 334–343.
[6]  Waheed AA, Freed EO (2009) Lipids and membrane microdomains in HIV-1 replication. Virus research 143: 162–176.
[7]  Bukrinsky M, Sviridov D (2006) Human immunodeficiency virus infection and macrophage cholesterol metabolism. Journal of leukocyte biology 80: 1044–1051.
[8]  Graham DR, Chertova E, Hilburn JM, Arthur LO, Hildreth JE (2003) Cholesterol depletion of human immunodeficiency virus type 1 and simian immunodeficiency virus with beta-cyclodextrin inactivates and permeabilizes the virions: evidence for virion-associated lipid rafts. Journal of virology 77: 8237–8248.
[9]  Liao Z, Graham DR, Hildreth JE (2003) Lipid rafts and HIV pathogenesis: virion-associated cholesterol is required for fusion and infection of susceptible cells. AIDS research and human retroviruses 19: 675–687.
[10]  Campbell SM, Crowe SM, Mak J (2002) Virion-associated cholesterol is critical for the maintenance of HIV-1 structure and infectivity. AIDS 16: 2253–2261.
[11]  Liao Z, Cimakasky LM, Hampton R, Nguyen DH, Hildreth JE (2001) Lipid rafts and HIV pathogenesis: host membrane cholesterol is required for infection by HIV type 1. AIDS research and human retroviruses 17: 1009–1019.
[12]  Ono A, Freed EO (2001) Plasma membrane rafts play a critical role in HIV-1 assembly and release. Proceedings of the National Academy of Sciences of the United States of America 98: 13925–13930.
[13]  Popik W, Alce TM, Au WC (2002) Human immunodeficiency virus type 1 uses lipid raft-colocalized CD4 and chemokine receptors for productive entry into CD4(+) T cells. Journal of virology 76: 4709–4722.
[14]  Brown DA, London E (1998) Structure and origin of ordered lipid domains in biological membranes. The Journal of membrane biology 164: 103–114.
[15]  Chan R, Uchil PD, Jin J, Shui G, Ott DE, et al. (2008) Retroviruses human immunodeficiency virus and murine leukemia virus are enriched in phosphoinositides. Journal of virology 82: 11228–11238.
[16]  Beer C, Pedersen L (2006) Amphotropic murine leukemia virus is preferentially attached to cholesterol-rich microdomains after binding to mouse fibroblasts. Virology journal 3: 21.
[17]  Li M, Yang C, Tong S, Weidmann A, Compans RW (2002) Palmitoylation of the murine leukemia virus envelope protein is critical for lipid raft association and surface expression. Journal of virology 76: 11845–11852.
[18]  Beer C, Pedersen L, Wirth M (2005) Amphotropic murine leukaemia virus envelope protein is associated with cholesterol-rich microdomains. Virology journal 2: 36.
[19]  Beer C, Andersen DS, Rojek A, Pedersen L (2005) Caveola-dependent endocytic entry of amphotropic murine leukemia virus. Journal of virology 79: 10776–10787.
[20]  Lu X, Silver J (2000) Ecotropic murine leukemia virus receptor is physically associated with caveolin and membrane rafts. Virology 276: 251–258.
[21]  Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, et al. (2006) Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS pathogens 2: e25.
[22]  Menendez-Arias L (2011) Evidence and controversies on the role of XMRV in prostate cancer and chronic fatigue syndrome. Reviews in medical virology 21: 3–17.
[23]  Mikovits JA, Lombardi VC, Pfost MA, Hagen KS, Ruscetti FW (2010) Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Virulence 1: 386–390.
[24]  Aloia AL, Sfanos KS, Isaacs WB, Zheng Q, Maldarelli F, et al. (2010) XMRV: a new virus in prostate cancer? Cancer research 70: 10028–10033.
[25]  Silverman RH, Nguyen C, Weight CJ, Klein EA (2010) The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. Nature reviews Urology 7: 392–402.
[26]  Paprotka T, Delviks-Frankenberry KA, Cingoz O, Martinez A, Kung HJ, et al. (2011) Recombinant origin of the retrovirus XMRV. Science 333: 97–101.
[27]  Qiu X, Swanson P, Luk KC, Tu B, Villinger F, et al. (2010) Characterization of antibodies elicited by XMRV infection and development of immunoassays useful for epidemiologic studies. Retrovirology 7: 68.
[28]  Karpas A (2004) Human retroviruses in leukaemia and AIDS: reflections on their discovery, biology and epidemiology. Biological reviews of the Cambridge Philosophical Society 79: 911–933.
[29]  Yang C, Compans RW (1996) Palmitoylation of the murine leukemia virus envelope glycoprotein transmembrane subunits. Virology 221: 87–97.
[30]  Olsen KE, Andersen KB (1999) Palmitoylation of the intracytoplasmic R peptide of the transmembrane envelope protein in Moloney murine leukemia virus. Journal of virology 73: 8975–8981.
[31]  Hensel J, Hintz M, Karas M, Linder D, Stahl B, et al. (1995) Localization of the palmitoylation site in the transmembrane protein p12E of Friend murine leukaemia virus. European journal of biochemistry/FEBS 232: 373–380.
[32]  Hadravova R, de Marco A, Ulbrich P, Stokrova J, Dolezal M, et al. (2011) In vitro assembly of virus-like particles of a Gammaretrovirus, the Murine Leukemia Virus (XMRV). Journal of virology 86: 1297–1306.
[33]  Datta SA, Zuo X, Clark PK, Campbell SJ, Wang YX, et al. (2011) Solution Properties of Murine Leukemia Virus Gag Protein: Differences from HIV-1 Gag. Journal of virology 85: 12733–12741.
[34]  Pickl WF, Pimentel-Muinos FX, Seed B (2001) Lipid rafts and pseudotyping. Journal of virology 75: 7175–7183.
[35]  Cingoz O, Paprotka T, Delviks-Frankenberry KA, Wildt S, Hu WS, et al. (2011) Characterization, Mapping and Distribution of the Two XMRV Parental Proviruses. Journal of virology 86: 328–338.
[36]  Nitta T, Kuznetsov Y, McPherson A, Fan H (2010) Murine leukemia virus glycosylated Gag (gPr80gag) facilitates interferon-sensitive virus release through lipid rafts. Proceedings of the National Academy of Sciences of the United States of America 107: 1190–1195.
[37]  Tang Y, Leao IC, Coleman EM, Broughton RS, Hildreth JE (2009) Deficiency of niemann-pick type C-1 protein impairs release of human immunodeficiency virus type 1 and results in Gag accumulation in late endosomal/lysosomal compartments. Journal of virology 83: 7982–7995.

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