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HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

机译：HIV-1抗体3BNC117抑制治疗中断期间人类的病毒反弹

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摘要

Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein(1), during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions, separated by 3 or 2 weeks, respectively, are generally well tolerated. Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals, emerging viruses show increased resistance, indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 mu g ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.
机译：HIV-1感染者中断联合抗逆转录病毒疗法会导致病毒快速反弹。在这里，我们报告IIa期开放临床试验的结果，该试验评估3BNC117，这是一种针对HIV-1 Env蛋白的CD4结合位点的广泛而有效的中和抗体（1），在13名感染HIV-1的个体中，分析治疗中断期间。参加了具有3BNC117敏感病毒外延培养物的参与者。结果显示，通常分别耐受2或4次30 mg kg（-1）3BNC117输注，分别间隔3或2周。输注与两次输注后病毒反弹延迟5-9周有关，与四次输注后长达19周相关，平均分别为6.7周和9.9周，而历史对照组为2.6周（P <0.00001） 。反弹病毒主要来自单个前病毒。在大多数个体中，新兴病毒显示出增加的抵抗力，表明逃逸。但是，直到抗体浓度降至20μg ml（-1）以下，仍有30％的参与者受到抑制，并且除这些个体中的一个以外，所有其他个体中出现的病毒均未显示出对3BCN117的明显抵抗力，这表明在9- 19周。我们得出的结论是，在人体分析治疗中断期间，3BNC117的使用会对潜伏水库中出现的HIV-1施加强大的选择性压力。

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  • 来源
    《Nature》 |2016年第7613期|556-560|共5页
  • 作者

    Scheid Johannes F.; Horwitz Joshua A.; Bar-On Yotam; Kreider Edward F.; Lu Ching-Lan; Lorenzi Julio C. C.; Feldmann Anna; Braunschweig Malte; Nogueira Lilian; Oliveira Thiago; Shimeliovich Irina; Patel Roshni; Burke Leah; Cohen Yehuda Z.; Hadrigan Sonya; Settler Allison; Witmer-Pack Maggi; West Anthony P. Jr.; Juelg Boris; Keler Tibor; Hawthorne Thomas; Zingman Barry; Gulick Roy M.; Pfeifer Nico; Learn Gerald H.; Seaman Michael S.; Bjorkman Pamela J.; Klein Florian; Schlesinger Sarah J.; Walker Bruce D.; Hahn Beatrice H.; Nussenzweig Michel C.; Caskey Marina;

  • 作者单位

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA|Massachusetts Gen Hosp, Boston, MA 02114 USA|Harvard Med Sch, Boston, MA 02114 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA|Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, Campus E1 4, D-66123 Saarbrcken, Germany;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Cornell Univ, Div Infect Dis, Weill Med Coll, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    CALTECH, Div Biol, Pasadena, CA 91125 USA;

    Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA;

    Celldex Therapeut Inc, Hampton, NJ 08827 USA;

    Celldex Therapeut Inc, Hampton, NJ 08827 USA;

    Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA;

    Cornell Univ, Div Infect Dis, Weill Med Coll, New York, NY 10065 USA;

    Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, Campus E1 4, D-66123 Saarbrcken, Germany;

    Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA|Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA;

    Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA;

    CALTECH, Div Biol, Pasadena, CA 91125 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA|Univ Cologne, Ctr Mol Med Cologne CMMC, Lab Expt Immunol, D-50931 Cologne, Germany|Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

    Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA|Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA;

    Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA|Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA|Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA;

    Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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