AAV-delivered HIV inhibitors for SHIV therapy

AAV 递送的 HIV 抑制剂用于 SHIV 治疗

基本信息

批准号：
10515149
负责人：
Matthew Ryan Gardner
金额：
$ 82.63万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515149
关键词：
Anti-Retroviral Agents Antibodies Antibody Response Binding Sites Clinical Trials Data Dependovirus Dose Engineering Evaluation HIV HIV Entry Inhibitors HIV-1 HIV-2 Human Immune Targeting Immune response Immune system In Vitro Individual Infection Infusion procedures Injecting drug user Intramuscular Lifting Macaca Macaca mulatta Mediating Monkeys Mus Muscle Muscle Cells Needle Sharing Pathway interactions Persons Pharmaceutical Preparations Pharmacotherapy Pilot Projects Proteins Reporting Resistance SIV Safety Serum Skeletal Muscle Technology Testing Therapeutic Time Tissues Transgenes Treatment Efficacy United States Viral Viral Load result Viral reservoir Viremia Virus Virus Replication Virus-like particle Woman adeno-associated viral vector antiretroviral therapy cohort design gene therapy humanized mouse immune checkpoint improved in vivo inhibitor men neutralizing antibody novel programmed cell death ligand 1 simian human immunodeficiency virus small molecule success therapy development transgene expression viral DNA viral RNA viral rebound

项目摘要

PROJECT SUMMARY More 10% of the new infections in the United States were from contaminated needle sharing among people who inject drugs (PWID). Importantly, only about 50% of men and 57% of women of the PWID group had suppressed viremia. Despite the lack of a sterilizing HIV-1 cure, antiretroviral drug therapies (ART) effectively suppress viral replication in people living with HIV-1. One limitation of ART is that these small molecule drugs cannot eliminate the viral reservoir. Broadly neutralizing antibodies (bNAbs) could supplement ART and be used to reduce the viral reservoir. Several studies have shown that a single dose of a bNAb can decrease viremia in HIV-1 infected individuals, with viral rebound occurring as the bNAb concentration decreases. Adeno-associated virus (AAV) vectors may provide the means for long-term expression of bNAbs at concentrations capable of maintaining viral suppression via intramuscular inoculations. However, we and others have shown that the emergence of anti-drug antibodies (ADA) to bNAbs limits their overall expression. Here, we show that we have made significant strides overcome this host immune response. First is through utilizing immune checkpoints that regulate immune system pathways. We observed a 21-fold increase in concentrations of the HIV-1 bNAb 10-1074 in rhesus macaques when macaques were co-inoculated with an AAV vector encoding rhesus macaque PD-L1. Second, we have developed a novel, HIV-1 entry inhibitor, eCD4-Ig, which tends to be more tolerated in rhesus macaques when expressed from AAV vectors. Unlike bNAbs, we have shown that AAV vectors encoding eCD4-Ig can express the inhibitor in macaques for over a year and the ADA response against eCD4-Ig decreases over time. Because eCD4-Ig neutralizes all HIV-1, HIV-2, and SIV isolates and is difficult to escape, it may be useful when included in a therapy strategy. Our pilot studies show that low concentrations AAV-expressed eCD4-Ig can suppress SHIV infection in rhesus macaques for two years, yet viremia is still detectable. This proposal combines our AAV advancements into a single strategy to determine whether AAV-expressed inhibitors can suppress a SHIV infection and reduce the viral reservoir. In Aim 1, we will assess the therapeutic efficacy of the combination of AAV-delivered eCD4-Ig and 10-1074 after ART is lifted in SHIV-infected rhesus macaques. In Aim 2, we will determine whether suppressing an established SHIV infection with AAV- delivered eCD4-Ig and 10-1074 results in a quantitatively different viral reservoir compared to ART. In Aim 3, we will improve the safety of AAV gene therapy by developing an irreversible “kill-switch” to turn off transgene expression.

项目概要美国超过 10% 的新感染病例是由于共用受污染的针头造成的重要的是，只有大约 50% 的男性和 57% 的女性是注射吸毒者。尽管缺乏有效的 HIV-1 治疗方法，但抗逆转录病毒药物疗法仍可抑制病毒血症。 (ART) 可有效抑制 HIV-1 感染者的病毒复制。ART 的局限性之一是。这些小分子药物不能消除病毒库的广泛中和抗体。多项研究表明，bNAb 可以补充 ART 并用于减少病毒储存。单剂 bNAb 可以降低 HIV-1 感染者的病毒血症，并导致病毒反弹腺相关病毒（AAV）载体可以提供 bNAb 在能够维持病毒浓度的浓度下长期表达的方法通过肌肉注射抑制然而，我们和其他人已经表明，出现了。 bNAb 的抗药物抗体 (ADA) 限制了它们的整体表达。克服这种宿主免疫反应的重大进展首先是通过利用免疫检查点。我们观察到 HIV-1 的浓度增加了 21 倍。当猕猴与编码 AAV 的载体共同接种时，恒河猴中出现 bNAb 10-1074 其次，我们开发了一种新型 HIV-1 进入抑制剂 eCD4-Ig。与 bNAb 不同的是，当从 AAV 载体表达时，恒河猴具有更高的耐受性。研究表明，编码 eCD4-Ig 的 AAV 载体可以在猕猴中表达抑制剂一年多并且针对 eCD4-Ig 的 ADA 反应会随着时间的推移而减弱，因为 eCD4-Ig 会中和所有 HIV-1， HIV-2 和 SIV 是分离的并且很难逃脱，如果将其纳入治疗策略中可能会很有用。我们的初步研究表明，低浓度 AAV 表达的 eCD4-Ig 可以抑制 SHIV 感染恒河猴两年，但仍可检测到病毒血症。该提案结合了我们的 AAV。确定 AAV 表达的抑制剂是否可以抑制 AAV 的单一策略的进展 SHIV 感染和减少病毒库在目标 1 中，我们将评估该药物的治疗效果。在感染 SHIV 的恒河猴中解除 ART 后 AAV 递送的 eCD4-Ig 和 10-1074 的组合在目标 2 中，我们将确定是否用 AAV- 抑制已确定的 SHIV 感染。与 ART 相比，递送的 eCD4-Ig 和 10-1074 导致病毒库数量不同。目标3，我们将通过开发不可逆的“终止开关”来提高AAV基因治疗的安全性关闭转基因表达。