Project 3:Optimal use of ART in establishing functional cures

项目 3：ART 在建立功能性治疗中的优化应用

• 批准号: 10381479
• 负责人: MICHAEL DAVID ALPERT
• 金额: $ 23.07万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381479
• 关键词: Anti-Retroviral Agents; Antibodies; Biological Products; CCR5 gene; CD8-Positive T-Lymphocytes; Cells; Chronic; Consequentialism; Data; Diagnosis; Disease remission; Equilibrium; Evolution; Formulation; Goals; HIV; HIV Infections; HIV Receptors; Healthcare; Immune response; Immunity; Immunologics; Injections; Intramuscular Injections; Kinetics; Macaca; Mediating; Outcome; Patients; Persons; Pharmaceutical Preparations; Resistance; Resolution; Response Latencies; Signal Transduction; Tail; Testing; Therapeutic; Time; Vaccines; Viral; Viral reservoir; Virus; Virus Latency; Virus Replication; Vision; Withdrawal; Work; antiretroviral therapy; cost; exhaustion; fitness; immune activation; improved; insight; neutralizing antibody; prevent; programs; simian human immunodeficiency virus; synergism; tool; treatment group; viral RNA

PROJECT SUMMARY (Project 3 – Optimal use of ART in establishing functional cures) In Project 3, Emmune, Inc. is collaborating with ViiV Healthcare to determine how antiretroviral therapy (ART) should be administered so as to maximize the ability of AAV-expressed therapeutics to establish robust functional cures and perhaps deplete the viral reservoir. ViiV Healthcare is developing long- acting cabotegravir, a product with several potential synergies with AAV-expressed anti-retroviral biologics developed by Emmune. This program seeks to ‘functionally cure’ HIV patients with a one-time intramuscular injection of an AAV-expressed therapeutic without the need for continuing antiretroviral therapy (ART). However, when AAV is first administered, ART is probably necessary to prevent the emergence of resistant viruses while the AAV-expressed therapeutic is present at suboptimal concentrations. Such resistance has been observed when broadly neutralizing antibodies (bNAbs) were administered to patients. The potential for resistance is an important reason why we have focused on eCD4-Ig, an immunoadhesin constructed from an antibody Fc and the parts of CD4 and CCR5. Because it closely emulates these HIV receptors, eCD4-Ig presents fundamental barriers to viral escape. Nonetheless, we have observed the emergence of partial resistance to eCD4-Ig, albeit associated with a high fitness cost. To prevent selection for partial resistance, we have pre-treated SHIV-infected macaques with ART before administering AAV expressing eCD4-Ig. When ART was subsequently withdrawn, transient ‘blips’ of viral RNA were occasionally detectable. We hypothesize that the quality of these functional cures can be improved by timing the application of ART so that host immune responses have not had time to wane prior introducing AAV expressing eCD4-Ig. Thus, AAV-expressed eCD4-Ig and peak host immune responses can work synergistically to deplete viral reservoirs and establish functional cures. In this project, we will determine whether ART is detrimental to depleting viral reservoirs and establishing functional cures in SHIV-infected macaques. To balance the need to prevent resistance with the benefits of synergy with host immune responses, we propose initiating ART and AAV- expressed eCD4-Ig at the same time. We also will determine whether a one-time administration of the long-acting formulation of cabotegravir, at the same time as AAV-eCD4-Ig is administered, is a practical solution for preventing partial resistance to eCD4-Ig. Conversely, we will also determine whether expression of eCD4-Ig prevents cabotegravir resistance during its so-called ‘long tail’, when cabotegravir concentrations are sub-clinical. Finally, these efforts will be supported by a panel of immunological studies that will provide a mechanistic insight into how ART, eCD4-Ig and host immunity collaborate to establish robust functional cures.

项目概要（项目3 -最佳使用ART建立功能性治疗） 在项目3中，Emmune，Inc.正在与ViiV Healthcare合作， (ART)应给予以使AAV表达的治疗剂建立免疫应答的能力最大化。 强大的功能治疗，也许耗尽病毒库。ViiV Healthcare正在开发长期- 作用于cabotegravir，一种与AAV表达的抗逆转录病毒药物具有几种潜在协同作用的产品 由Emmune开发的生物制剂。 该项目旨在通过一次性肌肉注射一种抗艾滋病药物， AAV表达的治疗，而不需要继续抗逆转录病毒治疗（ART）。然而，在这方面， 当首次施用AAV时，ART可能是防止耐药的出现所必需的。 病毒，而AAV表达的治疗剂以次优浓度存在。这种阻力 当向患者施用广泛中和抗体（bNAb）时，已经观察到。的 潜在的耐药性是我们关注eCD 4-IG（一种免疫粘附素）的重要原因 由抗体Fc和CD 4和CCR 5的部分构建。因为它紧密地模仿这些 HIV受体eCD 4-IG是病毒逃逸的基本屏障。然而，我们观察到， 对eCD 4-IG的部分抗性的出现，尽管与高适应性成本相关。 为了防止选择部分抗性，我们用ART预处理了SHIV感染的猕猴， 在施用表达eCD 4-IG的AAV之前。随后停止ART时，短暂的 偶尔可以检测到病毒RNA的“光点”。我们假设这些功能的质量 治疗可以通过选择ART的应用时间来改善，这样宿主的免疫反应就不会发生。 在引入表达eCD 4-IG的AAV之前的衰减时间。因此，AAV-表达的eCD 4-IG和峰值宿主 免疫反应可以协同作用以耗尽病毒储存库并建立功能性治疗。 在这个项目中，我们将确定ART是否不利于消耗病毒库， 在SHIV感染的猕猴中建立功能性治疗。为了平衡防止抵抗的需要 由于与宿主免疫应答协同的益处，我们建议启动ART和AAV- 同时表达eCD 4-IG。我们还将确定是否一次性管理 在施用AAV-eCD 4-IG的同时，卡博特韦的长效制剂是一种实用的药物。 用于防止对eCD 4-IG的部分抗性的溶液。相反，我们还将确定是否 eCD 4-IG的表达在其所谓的“长尾”期间防止了卡替拉韦耐药性， cabotegravir浓度是亚临床的。最后，这些努力将得到一个小组的支持， 免疫学研究将提供ART、eCD 4-IG和宿主免疫如何作用的机制性见解， 合作建立强大的功能性治疗。