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: 10625290
• 负责人: MICHAEL DAVID ALPERT
• 金额: $ 33.41万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625290
• 关键词: Anti-Retroviral Agents; Antibodies; Biological Products; CCR5 gene; CD8-Positive T-Lymphocytes; Cells; Chronic; Collaborations; 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; Probability; 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.

项目摘要(项目3--最佳使用抗逆转录病毒疗法建立功能性治疗) 在项目3中，Emmune，Inc.正在与医疗合作，以确定如何进行抗逆转录病毒治疗 应给予(ART)，以最大限度地提高AAV表达的疗法建立 强大的功能性治疗，也许会耗尽病毒库。欢跃医疗发展已久- 与甲型肝炎病毒表达的抗逆转录病毒具有多个潜在协同作用的代理卡波替格列韦 由Emmune开发的生物制品。 这一计划寻求通过一次性肌肉注射一次阿司匹林治疗艾滋病患者。 AAV-表达治疗性，不需要继续抗逆转录病毒治疗(ART)。然而， 当第一次使用AAV时，抗逆转录病毒疗法可能是必要的，以防止出现耐药 病毒，而AAV表达的治疗性药物存在于次优浓度。这样的抵抗 在给患者使用广谱中和抗体(BNAbs)时观察到。这个 潜在的耐药性是我们关注免疫粘附素eCD4-Ig的一个重要原因 由抗体Fc和CD4和CCR5的部分构成。因为它紧密地模仿了这些 艾滋病毒受体，eCD4-Ig是病毒逃逸的根本障碍。尽管如此，我们观察到 出现对eCD4-Ig的部分耐药性，尽管与高昂的健身成本有关。 为了防止出现部分抗药性，我们用抗逆转录病毒药物对感染了shv病毒的猕猴进行了预处理。 在接种表达eCD4-Ig的AAV之前。当艺术随后被撤回时，短暂的 偶尔也能检测到病毒核糖核酸的“斑点”。我们假设这些功能的性质 通过适时应用抗逆转录病毒疗法可以提高治愈率，使宿主的免疫反应不会 在引入表达eCD4-Ig的AAV之前，时间已经过去了。因此，AAV表达的eCD4-Ig和峰值宿主 免疫反应可以协同作用，耗尽病毒库并建立有效的治疗方法。 在这个项目中，我们将确定抗逆转录病毒疗法是否对耗尽病毒储藏和 为感染希沃克病毒的猕猴建立有效的治疗方法。为了平衡防止抵抗的需要 借助与宿主免疫反应的协同作用，我们建议启动ART和AAV- 同时表达eCD4-Ig。我们还将确定是否一次性管理 卡替格列韦长效制剂，与AAV-eCD4-Ig同时应用，是一种实用的 预防eCD4-Ig部分耐药的解决方案。相反，我们还将确定是否 ECD4-Ig的表达可防止卡替格韦在其所谓的“长尾”期间耐药，当 卡波替格韦的浓度是亚临床的。最后，这些努力将得到一个小组的支持 免疫学研究将提供对ART、eCD4-Ig和宿主免疫如何 合作建立强大的功能性治疗方法。