Therapeutic Applications of Broadly Neutralizing Anti-HIV-1 Antibodies to Clear Latently Infected Cells

广泛中和抗 HIV-1 抗体在清除潜伏感染细胞中的治疗应用

• 批准号: 8847152
• 负责人: Ariel Halper-Stromberg
• 金额: $ 4.81万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-10 至 2017-12-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847152
• 关键词: Affect; Antibodies; Antibody Therapy; Binding; Cells; Chronic; Dependence; Development; Emergency Situation; Exhibits; Exposure to; Goals; HIV-1; Immunity; Individual; Infection; Infection prevention; Life; Life Cycle Stages; Mediating; Modeling; Monkeys; Mus; Population; Prophylactic treatment; Proviruses; Relative (related person); Research; Staging; Therapeutic; Treatment Efficacy; Viral; Virion; Virus; antibody-dependent cell cytotoxicity; antiretroviral therapy; combat; comparative efficacy; improved; in vivo; killings; mouse model; neutralizing antibody; nonhuman primate; novel; pandemic disease; passive antibodies; prevent; prophylactic; public health relevance

 DESCRIPTION (provided by applicant The HIV-1 pandemic is a global emergency for which no cure exists. The early establishment of a latent reservoir of cells harboring replication competent integrated provirus remains the major barrier to a cure. The development of strategies to actively clear infected cells very early in infection could delay, or prevent reservor establishment in newly infected individuals, thereby lengthening the window in which post-exposure prophylaxis (PEP) is effective. The ability to reactivate and clear latently infected cell in chronically infected individuals could decrease reservoir size, thus reducing the lifelong dependence on ART in this population. In both cases, reduction of the latent reservoir is likely to require active killing of HIV-1 infected cells. Antibodies have the ability to mediate clearance of infected cells by antibody-dependent cellular cytotoxicity (ADCC). However, whether or not anti-HIV-1 antibodies can clear infected cells by ADCC in vivo remains unproven. The proposed research investigates the ability of broadly neutralizing anti-HIV-1 antibodies (bNAbs) to clear HIV-1 infected cells in humanized mice, with a specific focus on their ability to alter the establishment and/or size of the latent reservoir. Specifically, this research will investigate: (1 bNAbs' efficacy as post- exposure prophylaxis due to their ability to clear infected cells and prevent reservoir establishment, and (2) bNAbs ability to clear latently infected cells from an established infection when combined with latency reactivating agents.

 描述（由申请人提供）HIV-1大流行是一种全球性的紧急情况，目前尚无治愈方法。携带有复制能力的整合前病毒的细胞的潜伏储库的早期建立仍然是治愈的主要障碍。在感染早期主动清除感染细胞的策略的发展可以延迟或防止新感染个体中的储备建立，从而延长暴露后预防（PEP）有效的窗口。在慢性感染个体中重新激活和清除潜伏感染细胞的能力可以减少储库大小，从而减少该人群对ART的终身依赖。在这两种情况下，潜在储层的减少可能 需要主动杀死HIV-1感染细胞。抗体具有介导以下物质清除的能力： 通过抗体依赖性细胞毒性（ADCC）感染细胞。然而，抗HIV-1抗体是否可以通过ADCC在体内清除感染的细胞仍然没有得到证实。拟议的研究调查了广泛中和抗HIV-1抗体（bNAb）清除人源化小鼠中HIV-1感染细胞的能力，特别关注它们改变潜伏库的建立和/或大小的能力。具体而言，本研究将研究：（1）bNAb作为暴露后预防的功效，因为它们能够清除感染的细胞并防止储库建立，和（2）当与潜伏再活化剂组合时，bNAb从已建立的感染中清除潜伏感染的细胞的能力。