3BNC117 and 10-1074 to suppress HIV-1 replication and reduce the reservoir

项目摘要 联合抗逆转录病毒疗法(ART)在抑制病毒复制和预防 然而，它不能根除艾滋病毒-1感染，也不能加速消除 被感染的细胞。HIV-1在静止的记忆CD4T细胞中作为整合前体持续处于潜伏状态 艺术无法接触到的。目前正在评估几项根除战略，并在很大程度上消除这些战略。 抗体(BNAbs)代表着一种很有前途的新模式，特别是如果与潜伏期反转剂结合使用的话。 抗体与抗逆转录病毒疗法的不同之处在于，它们可以通过其Fc结构域招募免疫效应器功能 加速清除病毒和受感染的细胞。此外，免疫复合体是有效的免疫原， 可以促进宿主免疫反应的发展。被动使用早期的抗HIV-1 bNAbs已经 已经在人体上进行了评估，发现通常是安全的和耐受性良好的。而这些第一代人 中和抗体在临床前和临床环境中大多无效，选定的新一代 BNAbs对人源化小鼠和非人源化小鼠的预防感染和抑制活动性感染 灵长类(NHP)。3BNC117和10-1074是目前最有效的广谱中和抗体 可用。3BNC117靶向CD4结合位点，10-1074靶向HIV-1 gp120的V3环碱基。 在第一阶段临床研究中，到目前为止，3BNC117和10-1074总体上是安全的。一次输注 3BNC117抑制HIV-1病毒血症的平均对数拷贝数为1.48个/ml，而10-1074抑制HIV-1病毒血症的平均对数拷贝数为1.48个 当剂量为30 mg/kg时，病毒血症平均减少1.34拷贝/毫升。在接受抗逆转录病毒治疗的个体中进行评估时 在ART的分析中断(ATI)期间，3BNC117有效地延迟了抗体敏感性的反弹 来自HIV-1蓄水池的病毒。类似于临床前的发现，出现了耐药病毒株的选择。 当两种抗体中的任何一种单独注射时。3BNC117和10-1074的组合具有相加效应 并提供更广泛的病毒株覆盖范围。我们现在建议研究政府应否 3BNC117和10-1074可以通过激活宿主免疫来抑制复制和减少储存库 系统。设想的临床试验是一项评估抗逆转录病毒药物的I期、开放标签、随机研究。 已实现病毒感染的HIV感染者每月6次输注3BNC117和10-1074的活性 在艺术的存在或不存在的情况下，仅用艺术来压制。我们将对储集层进行定量评价 以及确定复制能力病毒库的遗传成分的定性方法。在……里面 此外，我们将评估3BNC117和10-1074是否调节HIV-1特异性免疫反应。

Project Summary Combination antiretroviral therapy (ART) is highly successful in suppressing viral replication and preventing disease progression, however it cannot eradicate HIV-1 infection, and it does not accelerate the elimination of infected cells. HIV-1 persists in a latent state as integrated proviruses in resting memory CD4+ T cells that are not accessible to ART. Several eradication strategies are currently being evaluated, and broadly neutralizing antibodies (bNAbs) represent a promising new modality, particularly if coupled with latency reversing agents. Antibodies differ from ART in that they can recruit immune effector functions through their Fc domains to accelerate clearance of viruses and infected cells. In addition, immune complexes are potent immunogens that can foster development of host immune responses. Passive administration of earlier anti-HIV-1 bNAbs has been evaluated in humans and found to be generally safe and well tolerated. While these first generation neutralizing antibodies were largely ineffective in preclinical and clinical settings, selected newer generation bNAbs can prevent infection and suppress active infection in humanized mice (hu-mice) and non-human primates (NHP). 3BNC117 and 10-1074 are two of most potent broadly neutralizing antibodies currently available. 3BNC117 targets the CD4 binding site and 10-1074 targets the base of the V3 loop of HIV-1 gp120. In phase 1 clinical studies, 3BNC117 and 10-1074 have been generally safe to date. A single infusion of 3BNC117 suppressed HIV-1 viremia by an average of 1.48 log copies/ml, while 10-1074 suppressed HIV-1 viremia by an average of 1.34 copies/ml when dosed at 30 mg/kg. When evaluated in ART-treated individuals during an analytical interruption of ART (ATI), 3BNC117 effectively delayed rebound of antibody sensitive viruses from the HIV-1 reservoir. Similar to preclinical findings, selection of resistant viral strains occurred when either antibody was administered alone. The combination of 3BNC117 and 10-1074 have additive effects and provide broader coverage of viral strains. We now propose to study whether the administration of 3BNC117 and 10-1074 can suppress replication and reduce the reservoir by engaging the host immune system. The envisioned clinical trial is a phase I, open label, randomized study to evaluate the antiretroviral activity of 6 monthly infusions of 3BNC117 and 10-1074 to HIV-infected subjects who have achieved viral suppression with ART alone, in the presence or absence of ART. We will evaluate the reservoir by quantitative and qualitative methods to determine the genetic composition of the replication-competent viral reservoir. In addition, we will evaluate if 3BNC117 and 10-1074 modulate HIV-1-specific immune responses.