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, 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
Nature. 2016 Jul 28;535(7613):556-60. doi: 10.1038/nature18929. Epub 2016 Jun 22.
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, 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 μg 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.
在感染HIV-1的个体中中断联合抗逆转录病毒疗法会导致病毒迅速反弹。在此，我们报告一项IIa期开放标签临床试验的结果，该试验评估了13名感染HIV-1的个体在分析性治疗中断期间使用3BNC117（一种针对HIV-1包膜蛋白CD4结合位点的广泛且强效的中和抗体）的情况。招募了具有3BNC117敏感病毒生长培养物的参与者。结果显示，分别相隔3周或2周进行的两次或四次30mg/kg的3BNC117输注通常耐受性良好。输注与两次输注后病毒反弹延迟5 - 9周、四次输注后延迟长达19周相关，平均分别为6.7周和9.9周，而历史对照为2.6周（P < 0.00001）。反弹病毒主要源自单个前病毒。在大多数个体中，新出现的病毒显示出耐药性增加，表明发生了逃逸。然而，30%的参与者在抗体浓度降至20μg/ml以下之前一直处于病毒抑制状态，并且除其中一人外，所有这些个体中出现的病毒对3BCN117均无明显耐药性，这表明在9 - 19周内未发生逃逸。我们得出结论，在人类分析性治疗中断期间，给予3BNC117会对从潜伏库中出现的HIV-1施加强大的选择压力。
