Overcoming pre-existing immunity to AAV to enhance AAV-based HIV immunotherapies

克服预先存在的 AAV 免疫力，增强基于 AAV 的 HIV 免疫疗法

• 批准号: 10626436
• 负责人: Mauricio de Aguiar Martins
• 金额: $ 89.65万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-05 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626436
• 关键词: AIDS clinical trial group; Address; Africa South of the Sahara; Animals; Antibodies; Area; Benchmarking; Biological Products; Bypass; Capsid; Cells; Circulation; Clinic; Clinical; Clinical Research; Clinical Trials; Country; Cross Reactions; Dependovirus; Developed Countries; Dose; Endopeptidases; Epidemic; Epidemiology; Excision; Exclusion; Fc Receptor; Genes; Genome; Geography; Goals; HIV; HIV Infections; HIV Vaccine Trials Network; HIV/AIDS; High Prevalence; Home; Human; Humoral Immunities; Immunity; Immunoglobulin G; Immunotherapy; Individual; Infection; Infusion procedures; Injections; Interruption; Intervention; Intramuscular; Knowledge; Macaca; Macaca mulatta; Mediating; Monitor; Monkeys; Monoclonal Antibodies; Monoclonal Antibody Therapy; Muscle; Muscle Cells; Persons; Plasmapheresis; Prevalence; Primates; Production; Research; Resistance; Role; SIV; Series; Seroprevalences; Serotyping; Serum; Testing; Time; Transgenes; Translating; Virus Diseases; Virus Replication; Vision; adeno-associated viral vector; antiretroviral therapy; clinically relevant; combat; cross reactivity; efficacy testing; experimental study; gene product; gene therapy; improved; in vivo; inhibitor; mindfulness; neonatal Fc receptor; nonhuman primate; pandemic disease; pharmacologic; preclinical study; prevent; seropositive; serosurvey; success; transgene expression; vector

PROJECT SUMMARY Adeno-associated virus (AAV)-mediated gene therapy with broadly (b) neutralizing (n) antibodies (Abs) holds great promise for preventing and treating HIV infection. This approach is unique in that host cells, after receiving the relevant genes through AAV transduction, can immediately begin to secrete bnAbs into the circulation. Because AAV is non-pathogenic and its genome persists in host cells, successful AAV transduction of long-lived cells, such as muscle cells, can result in continuous expression of bnAbs for years, possibly decades. Since realizing this vision in humans would dramatically simplify efforts to combat the HIV/AIDS pandemic, this project focuses on overcoming a key obstacle to the clinical use of AAV/bnAb therapy: the high prevalence of anti-AAV nAbs in humans. Anti-AAV nAbs target the AAV capsid and are mainly induced by natural infection with wild-type (WT) AAV, which is endemic in primates. AAV seroprevalence varies geographically, ranging from 30% to 100%, depending on the AAV serotype. Because of structural similarities among different capsids, nAbs induced by infection with WT AAV often cross-react with other AAV serotypes, including those used for gene therapy. This is problematic because, depending on the nAb titer, Ab-mediated neutralization of AAV vectors can reduce or even abrogate transduction. Hence, AAV seropositive (+) individuals are currently excluded from clinical trials of AAV-based gene therapies. These observations, viewed in the context of the 38 million people living with HIV (PLWH) worldwide who could benefit from AAV/bnAb therapy, highlight the need to develop strategies to overcome pre-existing anti-AAV nAbs. Here we propose a series of approaches to bypass humoral immunity to AAV in AAV(+) individuals, with the ultimate goal of expanding people’s access to AAV/bnAb therapy. This project has four specific aims. Our first aim is to identify the least prevalent muscle-tropic AAV capsid in sub- Saharan Africa, home of two thirds of all PLWH. Knowledge gained from this serosurvey would allow AAV(–) PLWH to benefit from AAV/bnAb therapies without any additional intervention. Aim 1 will also establish the range of pre-existing anti-AAV nAb titers that must be overcome to enable AAV transduction in field settings. Our second and third aims are to assess the extent to which transient depletion of serum IgG Abs can decrease anti-AAV nAb titers in AAV(+) rhesus macaques (RMs). Our final aim is to integrate the findings of Aims 1-3 by testing whether depleting pre-existing anti-AAV nAbs in RMs with pharmacologically controlled simian immunodeficiency virus (SIV) infection can enhance AAV-mediated delivery of eCD4-Ig–a bnAb-like molecule that potently neutralizes both HIV and SIV. Aim 4 will also assess the ability of AAV-expressed eCD4-Ig to maintain antiretroviral therapy- free control of SIV virus replication. Thus, this project will not only establish a blueprint for testing AAV-based HIV immunotherapies in the epicenter of the HIV/AIDS pandemic, but it will also expand our toolkit of interventions for evading pre-existing immunity to AAV. If successful, this research could bring us closer to achieving sustained AAV-driven production of anti-HIV biologics in people, regardless of AAV serostatus.

项目概要 使用广泛 (b) 中和 (n) 抗体 (Abs) 的腺相关病毒 (AAV) 介导的基因治疗 这种方法在宿主细胞中是独一无二的，对于预防和治疗艾滋病毒感染具有巨大的前景。 通过AAV转导接收相关基因，可以立即开始分泌bnAbs到 由于AAV是非致病性的并且其基因组持续存在于宿主细胞中，因此AAV能够成功转导。 长寿命细胞（例如肌肉细胞）的存在可以导致 bnAb 持续表达数年，可能 几十年来，在人类中实现这一愿景将大大简化抗击艾滋病毒/艾滋病的工作。 大流行期间，该项目的重点是克服 AAV/bnAb 疗法临床使用的一个关键障碍：高 抗 AAV nAb 在人类中的流行。抗 AAV nAb 靶向 AAV 衣壳，主要由天然诱导。 野生型 (WT) AAV 感染在灵长类动物中流行，AAV 血清流行率因地域而异。 范围从 30% 到 100%，取决于 AAV 血清型，因为不同血清型之间的结构相似。 WT AAV 感染诱导的衣壳、nAb 经常与其他 AAV 血清型（包括使用的血清型）发生交叉反应 对于基因治疗来说，这是有问题的，因为根据 nAb 滴度，AAV 介导的中和作用。 载体可以减少甚至消除转导，因此，AAV 血清阳性 (+) 个体目前被排除在外。 这些观察结果来自基于 AAV 的基因疗法的临床试验，是在 3800 万人的背景下观察的。 全世界可以从 AAV/bnAb 治疗中受益的艾滋病毒感染者 (PLWH) 强调需要开发 克服现有抗 AAV nAb 的策略在这里，我们提出了一系列绕过体液的方法。 AAV（+）个体对 AAV 的免疫力，最终目标是扩大人们获得 AAV/bnAb 治疗的机会。 该项目有四个具体目标，我们的第一个目标是确定亚组中最不常见的肌肉亲性 AAV 衣壳。 撒哈拉非洲是三分之二感染者的家园，从这次血清调查中获得的知识将允许 AAV(-)。 无需任何额外干预即可受益于 AAV/bnAb 疗法的 PLWH 也将确定该范围。 必须克服预先存在的抗 AAV nAb 滴度，才能在现场环境中实现 AAV 转导。 第三个目标是评估血清 IgG Ab 的瞬时消耗可在多大程度上降低抗 AAV nAb AAV(+) 恒河猴 (RM) 中的滴度 我们的最终目标是通过测试是否能够整合目标 1-3 的结果。 用药理学控制的猿猴免疫缺陷病毒消除 RM 中预先存在的抗 AAV nAb (SIV) 感染可以增强 AAV 介导的 eCD4-Ig 传递——一种 bnAb 样分子，可有效中和 HIV 和 SIV 还将评估 AAV 表达的 eCD4-Ig 维持抗逆转录病毒治疗的能力 - 自由控制SIV病毒复制因此，该项目不仅将建立一个基于AAV的测试蓝图。 艾滋病毒/艾滋病大流行中心的艾滋病毒免疫疗法，但它也将扩展我们的工具包 如果成功的话，这项研究可以使我们更接近于逃避 AAV 已有的免疫力。 无论 AAV 血清状态如何，都能在人体中实现由 AAV 驱动的抗 HIV 生物制剂的持续生产。