Susceptibility of the human retrovirus XMRV to antiretroviral inhibitors
Tóm tắt
XMRV (xenotropic murine leukemia virus-related virus) is the first known example of an exogenous gammaretrovirus that can infect humans. A limited number of reports suggest that XMRV is intrinsically resistant to many of the antiretroviral drugs used to treat HIV-1 infection, but is sensitive to a small subset of these inhibitors. In the present study, we used a novel marker transfer assay to directly compare the antiviral drug sensitivities of XMRV and HIV-1 under identical conditions in the same host cell type. We extend the findings of previous studies by showing that, in addition to AZT and tenofovir, XMRV and HIV-1 are equally sensitive to AZddA (3'-azido-2',3'-dideoxyadenosine), AZddG (3'-azido-2',3'-dideoxyguanosine) and adefovir. These results indicate that specific 3'-azido or acyclic nucleoside analog inhibitors of HIV-1 reverse transcriptase (RT) also block XMRV infection with comparable efficacy in vitro. Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors nevirapine and efavirenz and to inhibitors of HIV-1 protease. In addition, we show that the integrase inhibitors raltegravir and elvitegravir are active against XMRV, with EC50 values in the nanomolar range. Our analysis demonstrates that XMRV exhibits a distinct pattern of nucleoside analog susceptibility that correlates with the structure of the pseudosugar moiety and that XMRV is sensitive to a broader range of antiretroviral drugs than has previously been reported. We suggest that the divergent drug sensitivity profiles of XMRV and HIV-1 are partially explained by specific amino acid differences in their respective protease, RT and integrase sequences. Our data provide a basis for choosing specific antiretroviral drugs for clinical studies in XMRV-infected patients.
Tài liệu tham khảo
Coffin JM, Hughes SH, Varmus HE: Retroviruses. 1997, Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press
Blikstad V, Benachenhou F, Sperber GO, Blomberg J: Evolution of human endogenous retroviral sequences: a conceptual account. Cell Mol Life Sci. 2008, 65: 3348-3365. 10.1007/s00018-008-8495-2.
Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL: Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006, 2: e25-10.1371/journal.ppat.0020025.
Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H, Aepfelbacher M, Schlomm T: Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. J Clin Virol. 2008, 43: 277-283. 10.1016/j.jcv.2008.04.016.
Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR: XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proc Natl Acad Sci USA. 2009, 106: 16351-16356. 10.1073/pnas.0906922106.
Arnold RS, Makarova NV, Osunkoya AO, Suppiah S, Scott TA, Johnson NA, Bhosle SM, Liotta D, Hunter E, Marshall FF, Ly H, Molinaro RJ, Blackwell JL, Petros JA: XMRV infection in patients with prostate cancer: novel serologic assay and correlation with PCR and FISH. Urology. 2010, 75: 755-761. 10.1016/j.urology.2010.01.038.
Knouf EC, Metzger MJ, Mitchell PS, Arroyo JD, Chevillet JR, Tewari M, Miller AD: Multiple integrated copies and high-level production of the human retrovirus XMRV (xenotropic murine leukemia virus-related virus) from 22Rv1 prostate carcinoma cells. J Virol. 2009, 83: 7353-7356. 10.1128/JVI.00546-09.
Hong S, Klein EA, Das Gupta J, Hanke K, Weight CJ, Nguyen C, Gaughan C, Kim KA, Bannert N, Kirchhoff F, Munch J, Silverman RH: Fibrils of prostatic acid phosphatase fragments boost infections with XMRV (xenotropic murine leukemia virus-related virus), a human retrovirus associated with prostate cancer. J Virol. 2009, 83: 6995-7003. 10.1128/JVI.00268-09.
Rodriguez JJ, Goff SP: Xenotropic murine leukemia virus-related virus establishes an efficient spreading infection and exhibits enhanced transcriptional activity in prostate carcinoma cells. J Virol. 2010, 84: 2556-2562. 10.1128/JVI.01969-09.
Stieler K, Schulz C, Lavanya M, Aepfelbacher M, Stocking C, Fischer N: Host range and cellular tropism of the human exogenous gammaretrovirus XMRV. Virology. 2010, 399: 23-30. 10.1016/j.virol.2009.12.028.
Dong B, Kim S, Hong S, Das Gupta J, Malathi K, Klein EA, Ganem D, Derisi JL, Chow SA, Silverman RH: An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors. Proc Natl Acad Sci USA. 2007, 104: 1655-1660. 10.1073/pnas.0610291104.
Groom HC, Yap MW, Galao RP, Neil SJ, Bishop KN: Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors. Proc Natl Acad Sci USA. 2010, 107: 5166-5171. 10.1073/pnas.0913650107.
Metzger MJ, Holguin CJ, Mendoza R, Miller AD: The prostate cancer-associated human retrovirus XMRV lacks direct transforming activity but can induce low rates of transformation in cultured cells. J Virol. 2010, 84: 1874-1880. 10.1128/JVI.01941-09.
Kim S, Kim N, Dong B, Boren D, Lee SA, Das Gupta J, Gaughan C, Klein EA, Lee C, Silverman RH, Chow SA: Integration site preference of xenotropic murine leukemia virus-related virus, a new human retrovirus associated with prostate cancer. J Virol. 2008, 82: 9964-9977. 10.1128/JVI.01299-08.
Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA: Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science. 2009, 326: 585-589. 10.1126/science.1179052.
Groom HC, Boucherit VC, Makinson K, Randal E, Baptista S, Hagan S, Gow JW, Mattes FM, Breuer J, Kerr JR, Stoye JP, Bishop KN: Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology. 2010, 7: 10-10.1186/1742-4690-7-10.
Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N, Denner J, Miller K, Kurth R, Bannert N: Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology. 2009, 6: 92-10.1186/1742-4690-6-92.
Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A: Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One. 2010, 5: e8519-10.1371/journal.pone.0008519.
van Kuppeveld FJ, de Jong AS, Lanke KH, Verhaegh GW, Melchers WJ, Swanink CM, Bleijenberg G, Netea MG, Galama JM, van der Meer JW: Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ. 2010, 340: c1018-10.1136/bmj.c1018.
D'Arcy F, Foley R, Perry A, Marignol L, Lawler M, Gaffney E, Watson RGW, Fitzpatrick JM, Lynch TH: No evidence of XMRV in Irish prostate cancer patients with the R462Q mutation. European Urology Supplements. 2008, 271-10.1016/S1569-9056(08)60798-8. 7
Sakuma R, Sakuma T, Ohmine S, Silverman RH, Ikeda Y: Xenotropic murine leukemia virus-related virus is susceptible to AZT. Virology. 2010, 397: 1-6. 10.1016/j.virol.2009.11.013.
Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu WS, Pathak VK: Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs. J Virol. 2010, 84: 5719-5729. 10.1128/JVI.00134-10.
Singh IR, Gorzynski JE, Drobysheva D, Bassit L, Schinazi RF: Raltegravir is a potent inhibitor of XMRV, a virus implicated in prostate cancer and chronic fatigue syndrome. PLoS One. 2010, 5: e9948-10.1371/journal.pone.0009948.
Larder BA, Chesebro B, Richman DD: Susceptibilities of zidovudine-susceptible and -resistant human immunodeficiency virus isolates to antiviral agents determined by using a quantitative plaque reduction assay. Antimicrob Agents Chemother. 1990, 34: 436-441.
Miller AD, Bonham L, Alfano J, Kiem HP, Reynolds T, Wolgamot G: A novel murine retrovirus identified during testing for helper virus in human gene transfer trials. J Virol. 1996, 70: 1804-1809.
Hachiya A, Aizawa-Matsuoka S, Tanaka M, Takahashi Y, Ida S, Gatanaga H, Hirabayashi Y, Kojima A, Tatsumi M, Oka S: Rapid and simple phenotypic assay for drug susceptibility of human immunodeficiency virus type 1 using CCR5-expressing HeLa/CD4(+) cell clone 1-10 (MAGIC-5). Antimicrob Agents Chemother. 2001, 45: 495-501. 10.1128/AAC.45.2.495-501.2001.
Sramkoski RM, Pretlow TG, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, Marengo SR, Rhim JS, Zhang D, Jacobberger JW: A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 1999, 35: 403-409. 10.1007/s11626-999-0115-4.
Battini JL, Rasko JE, Miller AD: 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. 1999, 96: 1385-1390. 10.1073/pnas.96.4.1385.
Sluis-Cremer N, Koontz D, Bassit L, Hernandez-Santiago BI, Detorio M, Rapp KL, Amblard F, Bondada L, Grier J, Coats SJ, Schinazi RF, Mellors JW: Anti-human immunodeficiency virus activity, cross-resistance, cytotoxicity, and intracellular pharmacology of the 3'-azido-2',3'-dideoxypurine nucleosides. Antimicrob Agents Chemother. 2009, 53: 3715-3719. 10.1128/AAC.00392-09.
Ren J, Stammers DK: Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Virus Res. 2008, 134: 157-170. 10.1016/j.virusres.2007.12.018.
Oberg B: Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther. 1989, 40: 213-285. 10.1016/0163-7258(89)90097-1.
Jones GS, Yu F, Zeynalzadegan A, Hesselgesser J, Chen X, Chen J, Jin H, Kim CU, Wright M, Geleziunas R, Tsiang M: Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 2009, 53: 1194-1203. 10.1128/AAC.00984-08.
Strair RK, Nelson CJ, Mellors JW: Use of recombinant retroviruses to characterize the activity of antiretroviral compounds. J Virol. 1991, 65: 6339-6342.
Suruga Y, Makino M, Okada Y, Tanaka H, De Clercq E, Baba M: Prevention of murine AIDS development by (R)-9-(2-phosphonylmethoxypropyl)adenine. J Acquir Immune Defic Syndr Hum Retrovirol. 1998, 18: 316-322.
Powell SK, Artlip M, Kaloss M, Brazinski S, Lyons R, McGarrity GJ, Otto E: Efficacy of antiretroviral agents against murine replication-competent retrovirus infection in human cells. J Virol. 1999, 73: 8813-8816.
Rosenblum LL, Patton G, Grigg AR, Frater AJ, Cain D, Erlwein O, Hill CL, Clarke JR, McClure MO: Differential susceptibility of retroviruses to nucleoside analogues. Antivir Chem Chemother. 2001, 12: 91-97.
Feher A, Boross P, Sperka T, Miklossy G, Kadas J, Bagossi P, Oroszlan S, Weber IT, Tozser J: Characterization of the murine leukemia virus protease and its comparison with the human immunodeficiency virus type 1 protease. J Gen Virol. 2006, 87: 1321-1330. 10.1099/vir.0.81382-0.
Beck-Engeser GB, Eilat D, Harrer T, Jack HM, Wabl M: Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir. Proc Natl Acad Sci USA. 2009, 106: 20865-20870. 10.1073/pnas.0908074106.
Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Watanabe Y, Ohata Y, Doi S, Sato M, Kano M, Ikeda S, Matsuoka M: Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol. 2008, 82: 764-774. 10.1128/JVI.01534-07.
Johnson VA, Brun-Vezinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, Schapiro JM, Richman DD: Update of the drug resistance mutations in HIV-1: December 2009. Top HIV Med. 2009, 17: 138-145.
Winters MA, Merigan TC: Variants other than aspartic acid at codon 69 of the human immunodeficiency virus type 1 reverse transcriptase gene affect susceptibility to nucleoside analogs. Antimicrob Agents Chemother. 2001, 45: 2276-2279. 10.1128/AAC.45.8.2276-2279.2001.
Mouscadet JF, Delelis O, Marcelin AG, Tchertanov L: Resistance to HIV-1 integrase inhibitors: A structural perspective. Drug Resist Updat. 2010,
Halvas EK, Svarovskaia ES, Freed EO, Pathak VK: Wild-type and YMDD mutant murine leukemia virus reverse transcriptases are resistant to 2',3'-dideoxy-3'-thiacytidine. J Virol. 2000, 74: 6669-6674. 10.1128/JVI.74.14.6669-6674.2000.
Boyer PL, Gao HQ, Clark PK, Sarafianos SG, Arnold E, Hughes SH: YADD mutants of human immunodeficiency virus type 1 and Moloney murine leukemia virus reverse transcriptase are resistant to lamivudine triphosphate (3TCTP) in vitro. J Virol. 2001, 75: 6321-6328. 10.1128/JVI.75.14.6321-6328.2001.
Schinazi RF, Lloyd RM, Nguyen MH, Cannon DL, McMillan A, Ilksoy N, Chu CK, Liotta DC, Bazmi HZ, Mellors JW: Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother. 1993, 37: 875-881.
Meyer PR, Matsuura SE, Mian AM, So AG, Scott WA: A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell. 1999, 4: 35-43. 10.1016/S1097-2765(00)80185-9.
Meyer PR, Matsuura SE, So AG, Scott WA: Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. Proc Natl Acad Sci USA. 1998, 95: 13471-13476. 10.1073/pnas.95.23.13471.
St Clair MH, Richards CA, Spector T, Weinhold KJ, Miller WH, Langlois AJ, Furman PA: 3'-Azido-3'-deoxythymidine triphosphate as an inhibitor and substrate of purified human immunodeficiency virus reverse transcriptase. Antimicrob Agents Chemother. 1987, 31: 1972-1977.
Huang P, Farquhar D, Plunkett W: Selective action of 3'-azido-3'-deoxythymidine 5'-triphosphate on viral reverse transcriptases and human DNA polymerases. J Biol Chem. 1990, 265: 11914-11918.
Hazuda D, Iwamoto M, Wenning L: Emerging pharmacology: inhibitors of human immunodeficiency virus integration. Annu Rev Pharmacol Toxicol. 2009, 49: 377-394. 10.1146/annurev.pharmtox.011008.145553.
Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P: Retroviral intasome assembly and inhibition of DNA strand transfer. Nature. 2010, 464: 232-236. 10.1038/nature08784.
Rasheed S, Nelson-Rees WA, Toth EM, Arnstein P, Gardner MB: Characterization of a newly derived human sarcoma cell line (HT-1080). Cancer. 1974, 33: 1027-1033. 10.1002/1097-0142(197404)33:4<1027::AID-CNCR2820330419>3.0.CO;2-Z.
Miller AD, Rosman GJ: Improved retroviral vectors for gene transfer and expression. BioTechniques. 1989, 7: 980-982. 984-986, 989-990
Miller AD, Buttimore C: Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol. 1986, 6: 2895-2902.
Pear WS, Nolan GP, Scott ML, Baltimore D: Production of high-titer helper-free retroviruses by transient transfection. Proc Natl Acad Sci USA. 1993, 90: 8392-8396. 10.1073/pnas.90.18.8392.
Adachi A, Gendelman HE, Koenig S, Folks T, Willey R, Rabson A, Martin MA: Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol. 1986, 59: 284-291.
Smith RA, Anderson DJ, Preston BD: Purifying selection masks the mutational flexibility of HIV-1 reverse transcriptase. J Biol Chem. 2004, 279: 26726-26734. 10.1074/jbc.M314038200.
Shen L, Peterson S, Sedaghat AR, McMahon MA, Callender M, Zhang H, Zhou Y, Pitt E, Anderson KS, Acosta EP, Siliciano RF: Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat Med. 2008, 14: 762-766. 10.1038/nm1777.
Parikh UM, Koontz DL, Chu CK, Schinazi RF, Mellors JW: In vitro activity of structurally diverse nucleoside analogs against human immunodeficiency virus type 1 with the K65R mutation in reverse transcriptase. Antimicrob Agents Chemother. 2005, 49: 1139-1144. 10.1128/AAC.49.3.1139-1144.2005.
Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W, Tian H, Smith D, Winslow GA, Capon DJ, Whitcomb JM: A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2000, 44: 920-928. 10.1128/AAC.44.4.920-928.2000.
Image J Software. [http://rsb.info.nih.gov/ij]
EMBOSS Pairwise Alignment Algorithms. [http://www.ebi.ac.uk/Tools/emboss/align]
Cote ML, Roth MJ: Murine leukemia virus reverse transcriptase: structural comparison with HIV-1 reverse transcriptase. Virus Res. 2008, 134: 186-202. 10.1016/j.virusres.2008.01.001.
Poch O, Sauvaget I, Delarue M, Tordo N: Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J. 1989, 8: 3867-3874.
Bruenn JA: A structural and primary sequence comparison of the viral RNA-dependent RNA polymerases. Nucleic Acids Res. 2003, 31: 1821-1829. 10.1093/nar/gkg277.
Stanford University HIV Drug Resistance Database. [http://hivdb.stanford.edu/cgi-bin/INIResiNote.cgi]
Tamura K, Dudley J, Nei M, Kumar S: MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol. 2007, 24: 1596-1599. 10.1093/molbev/msm092.