AAV-delivered HIV inhibitors for SHIV therapy

AAV 递送的 HIV 抑制剂用于 SHIV 治疗

• 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
• 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

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.

项目摘要 在美国，更多的新感染中有10％来自受污染的针头共享 注射毒品的人（PWID）。重要的是，只有大约50％的男性和57％的PWID女性 组抑制了病毒血症。尽管缺乏抗逆转录病毒药物疗法的HIV-1治疗，但 （艺术）有效抑制HIV-1患者的病毒复制。艺术的一个限制是 这些小分子药物无法消除病毒储存剂。广泛中和抗体 （bnabs）可以补充艺术，并用于减少病毒疗效。几项研究表明 单剂量的BNAB可以减少病毒反弹的HIV-1感染个体的病毒血症 随着BNAB浓度的下降而发生。腺相关病毒（AAV）向量可能会提供 在能够维持病毒的浓度下长期表达BNAB的平均值 通过肌内接种抑制。但是，我们和其他人表明了 抗药物抗体（ADA）bnabs限制了其整体表达。在这里，我们证明我们已经做了 显着的步伐克服了该宿主免疫反应。首先是利用免疫检查点 调节免疫系统途径。我们观察到HIV-1的浓度增加了21倍 当猕猴与AAV矢量编码共接种时，BNAB 10-1074在恒河猕猴中 恒河猕猴PD-L1。其次，我们开发了一种新颖的HIV-1输入抑制剂ECD4-IG，它 从AAV载体表达时，在恒河猕猴中倾向于更耐受。与bnabs不同，我们 已经表明编码ECD4-Ig的AAV矢量可以在猕猴中表达抑制剂一年多 随着时间的流逝，对ECD4-Ig的ADA响应会减少。因为ECD4-Ig中和所有HIV-1，所以 HIV-2和SIV分离株，很难逃脱，当包括在治疗策略中时，它可能很有用。 我们的试点研究表明，低浓度AAV表达的ECD4-Ig可以抑制SHIV感染 猕猴已经两年了，但仍可以检测到病毒血症。该建议结合了我们的AAV 促进单一策略，以确定AAV表达的抑制剂是否可以抑制A SHIV感染并减少病毒储量。在AIM 1中，我们将评估 在Shiv感染的恒河猴中取消ART的AAV递送的ECD4-IG和10-1074的组合 猕猴。在AIM 2中，我们将确定是否会抑制具有AAV的已建立的SHIV感染 与ART相比，交付的ECD4-Ig和10-1074导致数量不同。在 AIM 3，我们将通过开发不可逆的“杀伤开关”来提高AAV基因疗法的安全性 不转化表达。