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    Graham Simmons, PhD

    TitleAssociate Professor
    SchoolUCSF School of Medicine
    DepartmentLaboratory Medicine
    Address270 Masonic
    San Francisco CA 94143

       Overview 
       Overview
      I am interested in new and emerging infections, particularly those that may threaten blood safety. My laboratory currently works on a number of viruses, including SARS-CoV, Chikungunya, Hepatitis B and C and the newly identified rhabdovirus, Bas-Congo virus, with a focus on viral entry and inhibition. We have performed a detailed molecular analysis of the entry of SARS-CoV and identified unique steps during entry that may be novel targets for antiviral therapies. We have developed new tools and assays for studying alphavirus virus entry and are adapting these to test novel antigens for Chikungunya virus vaccine production. We are also isolating and characterizing human neutralizing monoclonal antibodies for Chikungunya and HCV. Furthermore, we plan to characterize the B cell immune response to HCV and HBV, particularly following acute infection and HBV vaccine breakthrough infection. Finally, we are investigating the seroprevelance of Bas-Congo virus in Africa and performing basic analysis of this new virus, for example hunting the cellular receptor used for viral entry.


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       Publications
      Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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      1. Simmons G, Zmora P, Gierer S, Heurich A, Pöhlmann S. Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research. Antiviral Res. 2013 Dec; 100(3):605-14.
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      2. Selvarajah S, Sexton NR, Kahle KM, Fong RH, Mattia KA, Gardner J, Lu K, Liss NM, Salvador B, Tucker DF, Barnes T, Mabila M, Zhou X, Rossini G, Rucker JB, Sanders DA, Suhrbier A, Sambri V, Michault A, Muench MO, Doranz BJ, Simmons G. A neutralizing monoclonal antibody targeting the acid-sensitive region in chikungunya virus E2 protects from disease. PLoS Negl Trop Dis. 2013; 7(9):e2423.
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      3. Steffen I, Liss NM, Schneider BS, Fair JN, Chiu CY, Simmons G. Characterization of the Bas-Congo virus glycoprotein and its function in pseudotyped viruses. J Virol. 2013 Sep; 87(17):9558-68.
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      4. Gierer S, Bertram S, Kaup F, Wrensch F, Heurich A, Krämer-Kühl A, Welsch K, Winkler M, Meyer B, Drosten C, Dittmer U, von Hahn T, Simmons G, Hofmann H, Pöhlmann S. The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies. J Virol. 2013 May; 87(10):5502-11.
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      5. Salvador B, Sexton NR, Carrion R, Nunneley J, Patterson JL, Steffen I, Lu K, Muench MO, Lembo D, Simmons G. Filoviruses utilize glycosaminoglycans for their attachment to target cells. J Virol. 2013 Mar; 87(6):3295-304.
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      6. Simmons G. Filovirus entry. Adv Exp Med Biol. 2013; 790:83-94.
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      7. Zhou Y, Simmons G. Development of novel entry inhibitors targeting emerging viruses. Expert Rev Anti Infect Ther. 2012 Oct; 10(10):1129-38.
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      8. Grard G, Fair JN, Lee D, Slikas E, Steffen I, Muyembe JJ, Sittler T, Veeraraghavan N, Ruby JG, Wang C, Makuwa M, Mulembakani P, Tesh RB, Mazet J, Rimoin AW, Taylor T, Schneider BS, Simmons G, Delwart E, Wolfe ND, Chiu CY, Leroy EM. A novel rhabdovirus associated with acute hemorrhagic fever in central Africa. PLoS Pathog. 2012 Sep; 8(9):e1002924.
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      9. Lee D, Das Gupta J, Gaughan C, Steffen I, Tang N, Luk KC, Qiu X, Urisman A, Fischer N, Molinaro R, Broz M, Schochetman G, Klein EA, Ganem D, Derisi JL, Simmons G, Hackett J, Silverman RH, Chiu CY. In-depth investigation of archival and prospectively collected samples reveals no evidence for XMRV infection in prostate cancer. PLoS One. 2012; 7(9):e44954.
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      10. Glynn SA, Busch MP, Dodd RY, Katz LM, Stramer SL, Klein HG, Simmons G, Kleinman SH, Shurin SB. Emerging infectious agents and the nation's blood supply: responding to potential threats in the 21st century. Transfusion. 2013 Feb; 53(2):438-54.
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      11. Selvarajah S, Keating S, Heitman J, Lu K, Simmons G, Norris PJ, Operskalski E, Mosley JW, Busch MP. Detection of host immune responses in acute phase sera of spontaneous resolution versus persistent hepatitis C virus infection. J Gen Virol. 2012 Aug; 93(Pt 8):1673-9.
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      12. Zhou Y, Steffen I, Montalvo L, Lee TH, Zemel R, Switzer WM, Tang S, Jia H, Heneine W, Winkelman V, Tailor CS, Ikeda Y, Simmons G. Development and application of a high-throughput microneutralization assay: lack of xenotropic murine leukemia virus-related virus and/or murine leukemia virus detection in blood donors. Transfusion. 2012 Feb; 52(2):332-42.
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      13. Switzer WM, Zheng H, Simmons G, Zhou Y, Tang S, Shankar A, Kapusinszky B, Delwart EL, Heneine W. No evidence of murine leukemia virus-related viruses in live attenuated human vaccines. PLoS One. 2011; 6(12):e29223.
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      14. Steffen I, Tyrrell DL, Stein E, Montalvo L, Lee TH, Zhou Y, Lu K, Switzer WM, Tang S, Jia H, Hockman D, Santer DM, Logan M, Landi A, Law J, Houghton M, Simmons G. No evidence for XMRV nucleic acids, infectious virus or anti-XMRV antibodies in Canadian patients with chronic fatigue syndrome. PLoS One. 2011; 6(11):e27870.
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      15. Tang N, Frank A, Leckie G, Hackett J, Simmons G, Busch M, Abravaya K. Development of sensitive single-round pol or env RT-PCR assays to screen for XMRV in multiple sample types. J Virol Methods. 2012 Jan; 179(1):127-34.
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      16. Bertram S, Glowacka I, Müller MA, Lavender H, Gnirss K, Nehlmeier I, Niemeyer D, He Y, Simmons G, Drosten C, Soilleux EJ, Jahn O, Steffen I, Pöhlmann S. Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease. J Virol. 2011 Dec; 85(24):13363-72.
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      17. Simmons G, Glynn SA, Komaroff AL, Mikovits JA, Tobler LH, Hackett J, Tang N, Switzer WM, Heneine W, Hewlett IK, Zhao J, Lo SC, Alter HJ, Linnen JM, Gao K, Coffin JM, Kearney MF, Ruscetti FW, Pfost MA, Bethel J, Kleinman S, Holmberg JA, Busch MP. Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study. Science. 2011 Nov 11; 334(6057):814-7.
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      18. Zhou Y, Agudelo J, Lu K, Goetz DH, Hansell E, Chen YT, Roush WR, McKerrow J, Craik CS, Amberg SM, Simmons G. Inhibitors of SARS-CoV entry--identification using an internally-controlled dual envelope pseudovirion assay. Antiviral Res. 2011 Nov; 92(2):187-94.
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      19. Knox K, Carrigan D, Simmons G, Teque F, Zhou Y, Hackett J, Qiu X, Luk KC, Schochetman G, Knox A, Kogelnik AM, Levy JA. No evidence of murine-like gammaretroviruses in CFS patients previously identified as XMRV-infected. Science. 2011 Jul 1; 333(6038):94-7.
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      20. Simmons G, Bertram S, Glowacka I, Steffen I, Chaipan C, Agudelo J, Lu K, Rennekamp AJ, Hofmann H, Bates P, Pöhlmann S. Different host cell proteases activate the SARS-coronavirus spike-protein for cell-cell and virus-cell fusion. Virology. 2011 May 10; 413(2):265-74.
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      21. Simmons G, Glynn SA, Holmberg JA, Coffin JM, Hewlett IK, Lo SC, Mikovits JA, Switzer WM, Linnen JM, Busch MP. The Blood Xenotropic Murine Leukemia Virus-Related Virus Scientific Research Working Group: mission, progress, and plans. Transfusion. 2011 Mar; 51(3):643-53.
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      22. Kumaki Y, Wandersee MK, Smith AJ, Zhou Y, Simmons G, Nelson NM, Bailey KW, Vest ZG, Li JK, Chan PK, Smee DF, Barnard DL. Inhibition of severe acute respiratory syndrome coronavirus replication in a lethal SARS-CoV BALB/c mouse model by stinging nettle lectin, Urtica dioica agglutinin. Antiviral Res. 2011 Apr; 90(1):22-32.
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      23. Capon DJ, Kaneko N, Yoshimori T, Shimada T, Wurm FM, Hwang PK, Tong X, Adams SA, Simmons G, Sato TA, Tanaka K. Flexible antibodies with nonprotein hinges. Proc Jpn Acad Ser B Phys Biol Sci. 2011; 87(9):603-16.
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      24. Selvarajah S, Tobler LH, Simmons G, Busch MP. Host genetic basis for hepatitis C virus clearance: a role for blood collection centers. Curr Opin Hematol. 2010 Nov; 17(6):550-7.
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      25. Switzer WM, Jia H, Hohn O, Zheng H, Tang S, Shankar A, Bannert N, Simmons G, Hendry RM, Falkenberg VR, Reeves WC, Heneine W. Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States. Retrovirology. 2010; 7:57.
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      26. Zhou Y, Lu K, Pfefferle S, Bertram S, Glowacka I, Drosten C, Pöhlmann S, Simmons G. A single asparagine-linked glycosylation site of the severe acute respiratory syndrome coronavirus spike glycoprotein facilitates inhibition by mannose-binding lectin through multiple mechanisms. J Virol. 2010 Sep; 84(17):8753-64.
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      27. Chaipan C, Steffen I, Tsegaye TS, Bertram S, Glowacka I, Kato Y, Schmökel J, Münch J, Simmons G, Gerardy-Schahn R, Pöhlmann S. Incorporation of podoplanin into HIV released from HEK-293T cells, but not PBMC, is required for efficient binding to the attachment factor CLEC-2. Retrovirology. 2010; 7:47.
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      28. Glowacka I, Bertram S, Herzog P, Pfefferle S, Steffen I, Muench MO, Simmons G, Hofmann H, Kuri T, Weber F, Eichler J, Drosten C, Pöhlmann S. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol. 2010 Jan; 84(2):1198-205.
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      29. Salvador B, Zhou Y, Michault A, Muench MO, Simmons G. Characterization of Chikungunya pseudotyped viruses: Identification of refractory cell lines and demonstration of cellular tropism differences mediated by mutations in E1 glycoprotein. Virology. 2009 Oct 10; 393(1):33-41.
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      30. Kaletsky RL, Simmons G, Bates P. Proteolysis of the Ebola virus glycoproteins enhances virus binding and infectivity. J Virol. 2007 Dec; 81(24):13378-84.
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      31. Hofmann H, Simmons G, Rennekamp AJ, Chaipan C, Gramberg T, Heck E, Geier M, Wegele A, Marzi A, Bates P, Pöhlmann S. Highly conserved regions within the spike proteins of human coronaviruses 229E and NL63 determine recognition of their respective cellular receptors. J Virol. 2006 Sep; 80(17):8639-52.
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      32. Marzi A, Akhavan A, Simmons G, Gramberg T, Hofmann H, Bates P, Lingappa VR, Pöhlmann S. The signal peptide of the ebolavirus glycoprotein influences interaction with the cellular lectins DC-SIGN and DC-SIGNR. J Virol. 2006 Jul; 80(13):6305-17.
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      33. Qiu Z, Hingley ST, Simmons G, Yu C, Das Sarma J, Bates P, Weiss SR. Endosomal proteolysis by cathepsins is necessary for murine coronavirus mouse hepatitis virus type 2 spike-mediated entry. J Virol. 2006 Jun; 80(12):5768-76.
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      34. Amberg SM, Netter RC, Simmons G, Bates P. Expanded tropism and altered activation of a retroviral glycoprotein resistant to an entry inhibitor peptide. J Virol. 2006 Jan; 80(1):353-9.
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      35. Simmons G, Rennekamp AJ, Bates P. Proteolysis of SARS-associated coronavirus spike glycoprotein. Adv Exp Med Biol. 2006; 581:235-40.
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      36. Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A. 2005 Aug 16; 102(33):11876-81.
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      37. Temperton NJ, Chan PK, Simmons G, Zambon MC, Tedder RS, Takeuchi Y, Weiss RA. Longitudinally profiling neutralizing antibody response to SARS coronavirus with pseudotypes. Emerg Infect Dis. 2005 Mar; 11(3):411-6.
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      38. Marzi A, Gramberg T, Simmons G, Möller P, Rennekamp AJ, Krumbiegel M, Geier M, Eisemann J, Turza N, Saunier B, Steinkasserer A, Becker S, Bates P, Hofmann H, Pöhlmann S. DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus. J Virol. 2004 Nov; 78(21):12090-5.
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      39. Peters PJ, Bhattacharya J, Hibbitts S, Dittmar MT, Simmons G, Bell J, Simmonds P, Clapham PR. Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages. J Virol. 2004 Jul; 78(13):6915-26.
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      40. Simmons G, Reeves JD, Rennekamp AJ, Amberg SM, Piefer AJ, Bates P. Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc Natl Acad Sci U S A. 2004 Mar 23; 101(12):4240-5.
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      41. Simmons G, Lee A, Rennekamp AJ, Fan X, Bates P, Shen H. Identification of murine T-cell epitopes in Ebola virus nucleoprotein. Virology. 2004 Jan 5; 318(1):224-30.
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      42. Simmons G, Rennekamp AJ, Chai N, Vandenberghe LH, Riley JL, Bates P. Folate receptor alpha and caveolae are not required for Ebola virus glycoprotein-mediated viral infection. J Virol. 2003 Dec; 77(24):13433-8.
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      43. Simmons G, Reeves JD, Grogan CC, Vandenberghe LH, Baribaud F, Whitbeck JC, Burke E, Buchmeier MJ, Soilleux EJ, Riley JL, Doms RW, Bates P, Pöhlmann S. DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology. 2003 Jan 5; 305(1):115-23.
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      44. Lin G, Simmons G, Pöhlmann S, Baribaud F, Ni H, Leslie GJ, Haggarty BS, Bates P, Weissman D, Hoxie JA, Doms RW. Differential N-linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. J Virol. 2003 Jan; 77(2):1337-46.
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      45. Simmons G, Wool-Lewis RJ, Baribaud F, Netter RC, Bates P. Ebola virus glycoproteins induce global surface protein down-modulation and loss of cell adherence. J Virol. 2002 Mar; 76(5):2518-28.
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      46. Vyakarnam A, Eyeson J, Teo I, Zuckerman M, Babaahmady K, Schuitemaker H, Shaunak S, Rostron T, Rowland-Jones S, Simmons G, Clapham P. Evidence for a post-entry barrier to R5 HIV-1 infection of CD4 memory T cells. AIDS. 2001 Sep 7; 15(13):1613-26.
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      47. Blanpain C, Buser R, Power CA, Edgerton M, Buchanan C, Mack M, Simmons G, Clapham PR, Parmentier M, Proudfoot AE. A chimeric MIP-1alpha/RANTES protein demonstrates the use of different regions of the RANTES protein to bind and activate its receptors. J Leukoc Biol. 2001 Jun; 69(6):977-85.
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      48. Hayman A, Moss T, Simmons G, Arnold C, Holmes EC, Naylor-Adamson L, Hawkswell J, Allen K, Radford J, Nguyen-Van-Tam J, Balfe P. Phylogenetic analysis of multiple heterosexual transmission events involving subtype b of HIV type 1. AIDS Res Hum Retroviruses. 2001 May 20; 17(8):689-95.
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      49. Dejucq N, Simmons G, Clapham PR. T-cell line adaptation of human immunodeficiency virus type 1 strain SF162: effects on envelope, vpu and macrophage-tropism. J Gen Virol. 2000 Dec; 81(Pt 12):2899-904.
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      50. Simmons G, Reeves JD, Hibbitts S, Stine JT, Gray PW, Proudfoot AE, Clapham PR. Co-receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands. Immunol Rev. 2000 Oct; 177:112-26.
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      51. Sabroe I, Peck MJ, Van Keulen BJ, Jorritsma A, Simmons G, Clapham PR, Williams TJ, Pease JE. A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. J Biol Chem. 2000 Aug 25; 275(34):25985-92.
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      52. Elsner J, Mack M, Brühl H, Dulkys Y, Kimmig D, Simmons G, Clapham PR, Schlöndorff D, Kapp A, Wells TN, Proudfoot AE. Differential activation of CC chemokine receptors by AOP-RANTES. J Biol Chem. 2000 Mar 17; 275(11):7787-94.
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      53. Stine JT, Wood C, Hill M, Epp A, Raport CJ, Schweickart VL, Endo Y, Sasaki T, Simmons G, Boshoff C, Clapham P, Chang Y, Moore P, Gray PW, Chantry D. KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood. 2000 Feb 15; 95(4):1151-7.
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      54. Reeves JD, Simmons G. Chemokine inhibition of HIV infection. Methods Mol Biol. 2000; 138:209-22.
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      55. Dejucq N, Simmons G, Clapham PR. Expanded tropism of primary human immunodeficiency virus type 1 R5 strains to CD4(+) T-cell lines determined by the capacity to exploit low concentrations of CCR5. J Virol. 1999 Sep; 73(9):7842-7.
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      56. Reeves JD, Hibbitts S, Simmons G, McKnight A, Azevedo-Pereira JM, Moniz-Pereira J, Clapham PR. Primary human immunodeficiency virus type 2 (HIV-2) isolates infect CD4-negative cells via CCR5 and CXCR4: comparison with HIV-1 and simian immunodeficiency virus and relevance to cell tropism in vivo. J Virol. 1999 Sep; 73(9):7795-804.
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      57. Hibbitts S, Reeves JD, Simmons G, Gray PW, Epstein LG, Schols D, de Clercq E, Wells TN, Proudfoot AE, Clapham PR. Coreceptor ligand inhibition of fetal brain cell infection by HIV type 1. AIDS Res Hum Retroviruses. 1999 Jul 20; 15(11):989-1000.
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      58. Clapham PR, Reeves JD, Simmons G, Dejucq N, Hibbitts S, McKnight A. HIV coreceptors, cell tropism and inhibition by chemokine receptor ligands. Mol Membr Biol. 1999 Jan-Mar; 16(1):49-55.
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      59. Simmons G, Reeves JD, McKnight A, Dejucq N, Hibbitts S, Power CA, Aarons E, Schols D, De Clercq E, Proudfoot AE, Clapham PR. CXCR4 as a functional coreceptor for human immunodeficiency virus type 1 infection of primary macrophages. J Virol. 1998 Oct; 72(10):8453-7.
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      60. Mack M, Luckow B, Nelson PJ, Cihak J, Simmons G, Clapham PR, Signoret N, Marsh M, Stangassinger M, Borlat F, Wells TN, Schlöndorff D, Proudfoot AE. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J Exp Med. 1998 Apr 20; 187(8):1215-24.
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      61. Dittmar MT, Simmons G, Hibbitts S, O'Hare M, Louisirirotchanakul S, Beddows S, Weber J, Clapham PR, Weiss RA. Langerhans cell tropism of human immunodeficiency virus type 1 subtype A through F isolates derived from different transmission groups. J Virol. 1997 Oct; 71(10):8008-13.
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      62. Kledal TN, Rosenkilde MM, Coulin F, Simmons G, Johnsen AH, Alouani S, Power CA, Lüttichau HR, Gerstoft J, Clapham PR, Clark-Lewis I, Wells TN, Schwartz TW. A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science. 1997 Sep 12; 277(5332):1656-9.
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      63. Picard L, Simmons G, Power CA, Meyer A, Weiss RA, Clapham PR. Multiple extracellular domains of CCR-5 contribute to human immunodeficiency virus type 1 entry and fusion. J Virol. 1997 Jul; 71(7):5003-11.
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      64. Dittmar MT, Simmons G, Donaldson Y, Simmonds P, Clapham PR, Schulz TF, Weiss RA. Biological characterization of human immunodeficiency virus type 1 clones derived from different organs of an AIDS patient by long-range PCR. J Virol. 1997 Jul; 71(7):5140-7.
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      65. Reeves JD, McKnight A, Potempa S, Simmons G, Gray PW, Power CA, Wells T, Weiss RA, Talbot SJ. CD4-independent infection by HIV-2 (ROD/B): use of the 7-transmembrane receptors CXCR-4, CCR-3, and V28 for entry. Virology. 1997 Apr 28; 231(1):130-4.
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      66. Simmons G, Clapham PR, Picard L, Offord RE, Rosenkilde MM, Schwartz TW, Buser R, Wells TN, Proudfoot AE. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science. 1997 Apr 11; 276(5310):276-9.
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      67. Dittmar MT, McKnight A, Simmons G, Clapham PR, Weiss RA, Simmonds P. HIV-1 tropism and co-receptor use. Nature. 1997 Feb 6; 385(6616):495-6.
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      68. McKnight A, Wilkinson D, Simmons G, Talbot S, Picard L, Ahuja M, Marsh M, Hoxie JA, Clapham PR. Inhibition of human immunodeficiency virus fusion by a monoclonal antibody to a coreceptor (CXCR4) is both cell type and virus strain dependent. J Virol. 1997 Feb; 71(2):1692-6.
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      69. Simmons G, Wilkinson D, Reeves JD, Dittmar MT, Beddows S, Weber J, Carnegie G, Desselberger U, Gray PW, Weiss RA, Clapham PR. Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry. J Virol. 1996 Dec; 70(12):8355-60.
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      70. McKnight A, Shotton C, Cordell J, Jones I, Simmons G, Clapham PR. Location, exposure, and conservation of neutralizing and nonneutralizing epitopes on human immunodeficiency virus type 2 SU glycoprotein. J Virol. 1996 Jul; 70(7):4598-606.
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      71. Simmons G, McKnight A, Takeuchi Y, Hoshino H, Clapham PR. Cell-to-cell fusion, but not virus entry in macrophages by T-cell line tropic HIV-1 strains: a V3 loop-determined restriction. Virology. 1995 Jun 1; 209(2):696-700.
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      72. Clapham P, McKnight A, Simmons G, Weiss R. Is CD4 sufficient for HIV entry? Cell surface molecules involved in HIV infection. Philos Trans R Soc Lond B Biol Sci. 1993 Oct 29; 342(1299):67-73.
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