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

通过 bNAb 和生物制剂的组合对 HIV-1 进行免疫控制。

• 批准号: 10544484
• 负责人: Marina Caskey
• 金额: $ 159.68万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544484
• 关键词: Acceleration; Adult; Aftercare; Amino Acids; Animal Model; Animal Testing; Animals; Antibodies; Antibody-Dependent Enhancement; Antigen Presentation; Antigen-Antibody Complex; Antigens; B-Cell Lymphomas; BLR1 gene; Binding; Binding Sites; Biological Assay; Biological Products; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cells; Cellular Immunity; Clinical Research; Development; Disease Progression; Disease remission; Dose; Drug Kinetics; Fc domain; Fostering; Frequencies; Genetic; Genetic Transcription; HIV; HIV Envelope Protein gp120; HIV-1; Half-Life; Health; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunologics; Immunotherapy; Impaired cognition; In Vitro; Individual; Indolent; Infection; Infusion procedures; Innate Immune Response; Interleukin-15; Interruption; Intervention; Macaca; Measures; Mediating; Modeling; Monoclonal Antibodies; Mus; Mutation; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Patients; Persons; Phase I/II Clinical Trial; Pilot Projects; Plasma; Proliferating; Property; Provirus Integration; Qualitative Methods; Refractory; Relapse; SIV; Safety; T cell response; Testing; Time; V3 Loop; Vaccines; Variant; Viral; Viral Physiology; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Replication; adaptive immune response; anti-CD20; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; cancer cell; comorbidity; cytotoxic; healthy volunteer; immunological status; immunoregulation; improved; lymph nodes; neutralizing antibody; nonhuman primate; novel; peripheral blood; prevent; recruit; response; rituximab; simian human immunodeficiency virus; success; trafficking

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.

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， 随着疾病的进展，HIV-1在潜伏感染细胞的长期储存库中持续存在，这些细胞含有整合的前病毒 这些疾病是可以重新激活的，导致终生需要抗逆转录病毒治疗。 或诱导HIV-1长期免治疗缓解至关重要。广泛中和抗体（bNAb） 因为它们可以通过其Fc结构域募集免疫效应子功能以加速清除 病毒和受感染细胞的混合物。此外，免疫复合物是有效的免疫原， 宿主免疫反应的发展。3BNC117和10 - 1074是与CD4结合位点结合的bNAb （CD4bs）和HIV-1包膜gp-120中V3环的碱基。两种抗体都显示出 并在动物模型中保护或抑制感染。给药时 早期嵌合猴/人免疫缺陷病毒（SHIV）感染，3BNC 117和10 - 1074导致持续的 在大约一半的测试动物中进行病毒学控制。这种效应是由于CD8 + T细胞介导的对 病毒血症，表明bNAb具有免疫增强作用。在感染艾滋病毒的成年人中， 3BNC 117和10 - 1074在6周内在个体中维持病毒抑制平均21周 携带抗体敏感病毒，包括两名继续维持病毒抑制的人， ART停药后至少11个月。bNAb的潜在免疫调节作用是 这取决于抗原的可用性。完全抑制性ART降低了感染细胞的频率 表达包膜至似乎太低而不能诱导免疫的水平。相反，bNAb介导的病毒 抑制可能允许足够的抗原表达以触发免疫效应，并且这些效应可能是 当bNAb与已知调节免疫反应的分子联合使用时， 并诱导病毒转录。我们建议使用N-803来测试这些概念，N-803是一种白细胞介素-15超级激动剂， 其具有免疫调节特性，例如增强抗体依赖性细胞介导的 细胞毒性，并诱导HIV-1再活化。该项目旨在进行两项临床研究，以评估 3BNC 117和10 - 1074的长效（"LS"）变体的组合在病毒血症HIV-1中的抗病毒活性 感染的个体，并评估这种长效双bNAb组合产生持续的 在ART中断期间给予IL-15超激动剂N-803时的病毒缓解。