Immunologic control of HIV-1 through combination bNAbs and biologics.

项目摘要 尽管抗逆转录病毒疗法(ART)在抑制病毒复制和预防疾病方面取得了成功 进展中，HIV-1持续存在于潜伏感染细胞的长期蓄水池中，这些细胞携带整合的前病毒 它可以被重新激活，导致ART的终身需求。努力确定消除贫穷的战略 或者诱导艾滋病毒-1长期无需治疗的缓解是至关重要的。广谱中和抗体(BNAbs)不同 来自ART，因为它们可以通过其Fc结构域招募免疫效应器功能来加速清除 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。3BNC117和10-1074是与CD4结合位点结合的bNAbs (CD4bs)和HIV-1包膜GP-120中V3环的碱基。这两种抗体都表现出非凡的广泛性 和体外效力，并在动物模型中预防或抑制感染。在以下情况下给药 早期嵌合猴/人类免疫缺陷病毒感染，3BNC117和10-1074导致持续 在大约一半的测试动物中进行了病毒学控制。这一效应是由于CD8+T细胞介导的 病毒血症，提示bNAbs具有免疫增强作用。在感染艾滋病毒的成年人中，三剂 3BNC117和10-1074在6周内在个体中平均保持病毒抑制21周 携带抗体敏感病毒，包括两名继续保持病毒抑制的人 ART停产后至少11个月。BNAbs的潜在免疫调节作用是 依赖于抗原的可用性。完全抑制ART可降低感染细胞的频率 表达包膜的水平似乎太低，不能诱导免疫。相比之下，bNAb介导的病毒 抑制可能允许足够的抗原表达来触发免疫效应，而这些效应很可能 当bNAbs与已知的调节免疫反应的分子结合使用时，将得到增强 并诱导病毒转录。我们建议使用白细胞介素15超激动剂N-803来测试这些概念， 它具有免疫调节特性，如增强抗体依赖的细胞介导性 细胞毒性，并诱导HIV-1重新激活。本项目旨在进行两项临床研究，以评估 3BNC117和10-1074长效(LS)变异体组合在病毒型HIV中的抗病毒活性 并评估这种长效双bNAb组合产生持续的 在ART中断期间使用IL-15超级激动剂N-803时病毒缓解。

Project Summary Despite the success of antiretroviral therapy (ART) in suppressing viral replication and preventing disease progression, HIV-1 persists in a long-lived reservoir of latently infected cells that harbor integrated proviruses which can be reactivated, resulting in the lifelong requirement of ART. Efforts to identify strategies to eradicate or induce treatment-free long-term HIV-1 remission are critical. Broadly neutralizing antibodies (bNAbs) 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. 3BNC117 and 10-1074 are bNAbs that bind to the CD4 binding site (CD4bs) and to the base of the V3 loop in HIV-1 envelope gp-120. Both antibodies show exceptional breadth and potency in vitro, and protect against or suppress infection in animal models. When administered during early chimeric simian/human immunodeficiency virus (SHIV) infection, 3BNC117 and 10-1074 led to sustained virologic control in about half of the tested animals. This effect was due to CD8+ T cell mediated control of viremia, suggesting that the bNAbs exerted immune enhancing effects. In HIV-infected adults, three doses 3BNC117 and 10-1074 over 6 weeks maintained viral suppression for an average of 21 weeks in individuals harboring antibody-sensitive viruses, including two individuals who continued to maintain viral suppression for at least 11 months after ART discontinuation. The potential immune modulatory effects of bNAbs are dependent of the availability of antigen. Fully suppressive ART reduces the frequency of infected cells expressing envelope to levels that appear to be too low to induce immunity. In contrast, bNAb-mediated viral suppression may allow sufficient antigen expression to trigger immunologic effects, and these effects are likely to be enhanced when bNAbs are used in combination with molecules known to modulate immune responses and induce viral transcription. We propose to test these concepts using N-803, an interleukin-15 superagonist, which has immune modulatory properties, such as enhancement of antibody-dependent cell-mediated cytotoxicity, and induces HIV-1 reactivation. This project aims to conduct two clinical studies to evaluate the antiviral activity of the combination of the long-acting (“LS”) variants of 3BNC117 and 10-1074 in viremic HIV- infected individuals, and to assess the ability of this long-acting dual-bNAb combination to produce sustained viral remission when administered with the IL-15 superagonist, N-803, during ART interruption.