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.

项目总结 腺相关病毒介导的广谱中和抗体基因治疗 为预防和治疗艾滋病毒感染带来了巨大的希望。这种方法是独一无二的，因为宿主细胞在 通过AAV转导获得相关基因，可以立即开始将bNAbs分泌到 发行量。由于AAV是非致病性的，其基因组持续存在于宿主细胞中，因此成功的AAV转导 长寿命细胞，如肌肉细胞，可以导致bNAbs的持续表达多年，可能 几十年。因为在人类身上实现这一愿景将极大地简化抗击艾滋病毒/艾滋病的努力 在大流行期间，该项目专注于克服AAV/bNab疗法临床应用的一个关键障碍：高 抗AAV nabs在人类中的流行率。抗AAV-NAb针对AAV衣壳，主要由自然诱导 感染野生型(WT)AAV，这是灵长类动物的地方病。AAV血清阳性率因地域而异， 根据AAV的血清型，从30%到100%不等。因为不同组织之间的结构相似 由感染WT AAV引起的衣壳、NAB经常与其他AAV血清型发生交叉反应，包括所使用的AAV血清型 用于基因治疗。这是有问题的，因为根据NAB滴度，抗体介导的AAV中和 载体可以减少甚至取消转导。因此，AAV血清阳性(+)的个人目前被排除在外。 来自基于AAV的基因疗法的临床试验。在3800万人的背景下来看，这些观察结果 全球可受益于AAV/bNab疗法的艾滋病毒携带者(PLWH)强调了发展的必要性 克服预先存在的反AAV nabs的战略。在这里，我们提出了一系列绕过幽默的方法 AAV(+)个体对AAV的免疫力，最终目标是扩大人们获得AAV/bNab疗法的机会。 这个项目有四个具体目标。我们的第一个目标是确定最不流行的嗜肌性AAV衣壳在亚型 撒哈拉非洲，三分之二的PLWH的家园。从这次血清调查中获得的知识将使AAV(-) PLWH将受益于AAV/bNab疗法，而无需任何额外干预。目标一号也将建立射程 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。我们的第二个 第三个目的是评估短暂的血清免疫球蛋白抗体耗尽可以降低抗AAV-NAB的程度 AAV(+)恒河猴的滴度(RMS)。我们的最终目标是整合目标1-3的结果，方法是测试 用药物控制的猴免疫缺陷病毒耗尽RMS中预先存在的抗AAVNAb (SIV)感染可以增强AAV介导的eCD4-Ig-一种类似bNab的分子的传递，这种分子可以有效地中和 包括艾滋病毒和SIV。AIM 4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，该项目不仅将建立基于AAV的测试蓝图 艾滋病毒免疫疗法在艾滋病毒/艾滋病大流行的震中，但它也将扩大我们的工具包 逃避预先存在的对AAV免疫的干预措施。如果成功，这项研究可能会让我们更接近 在人类中实现由AAV驱动的抗艾滋病毒生物制品的持续生产，而无论AAV血清状态如何。