Modeling the HIV latent reservoir, latency reversal and immunotherapeutics for HIV cure

为 HIV 治愈建立 HIV 潜伏库、潜伏期逆转和免疫疗法的模型

• 批准号: 10653712
• 负责人: Ruian Ke
• 金额: $ 58.95万
• 依托单位: TRIAD NATIONAL SECURITY, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653712
• 关键词: Acceleration; Address; Affinity; Aftercare; Agonist; Antibodies; Binding; Biological; Biological Markers; Bispecific Antibodies; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Characteristics; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Complex; Coupled; Data; Data Set; Development; Disease remission; Effectiveness; Effector Cell; Exhibits; Favorable Clinical Outcome; Foundations; Future; Grant; HIV; HIV-1; Immune; Immune response; Immune system; Immunologic Markers; Immunotherapeutic agent; In Vitro; Individual; Integration Host Factors; Interruption; Intervention; Knowledge; Macaca; Macaca mulatta; Measurement; Measures; Medical; Modeling; Outcome; Parameter Estimation; Patients; Prediction of Response to Therapy; Public Health; Research; Role; System; TLR7 gene; Testing; Therapeutic Intervention; Treatment outcome; Viral; Viral Load result; Withholding Treatment; Work; acute infection; antiretroviral therapy; design; detection limit; effective intervention; effective therapy; experimental study; in vivo; latent HIV reservoir; mathematical model; neutralizing antibody; next generation; outcome prediction; pandemic disease; patient population; rational design; response; therapeutic development; therapeutic vaccine; therapeutically effective; tool; treatment strategy; viral rebound

SUMMARY A major barrier to HIV cure is the reservoir of latently infected cells that persists in patients treated with highly potent antiretroviral treatment (ART). Activation of these latently infected cells can lead to HIV rebound in the absence of ART. In clinical trials, HIV exhibits widely different dynamics after ART cessation. HIV rebounds rapidly in most individuals, whereas in a small fraction of individuals, prolonged HIV remission or post-treatment control (PTC) is achieved. Despite intensive research, we lack a clear and coherent understanding of the determinants of viral control or the duration of HIV remission after ART, which hinders the development of effective therapeutic strategies to achieve a ‘functional’ cure and ultimately a sterilizing cure. This grant addresses this gap in knowledge. Our central hypothesis is that PTC is not solely driven by a single factor; rather, it is a phenomenon emerging from complex nonlinear interactions between the immune response and the latent reservoir, including both the replication competent reservoir and the defective reservoir. Understanding this dynamical interaction will be key to develop effective interventions to achieve favorable clinical outcomes. We will first delineate the roles of these interactions in determining viral control through integration of recent biological findings into a mechanistic mathematical model. We will validate this model using clinical data from post-treatment controllers and non-controllers, correlate estimated model parameters with measured biological and immunological markers to identify patient characteristics that predict PTC. Further, we will estimate the mode of action and quantify the efficacy of a next-generation latency reversing agent (LRA), AZD5582, and a class of promising bispecific antibody-based immunotherapeutics, the Dual-Affinity Re-Targeting molecules. Finally, we will integrate models of how these agents work with a model of the interaction of the latent reservoir with the immune system to evaluate and predict the impact of combinations of LRAs and immunotherapeutics on the reservoir and on clinical outcomes. Altogether, our work will provide a theoretical foundation for 1) understanding HIV control and rebound dynamics after ART, 2) identifying patients who are likely to achieve PTC, 3) estimating/predicting the impact of therapeutic interventions such as LRAs and/or immunotherapeutics, and 4) suggesting effective interventions to achieve a ‘functional’ cure according to patient characteristics.

概括 HIV治愈的一个主要障碍是治疗患者体内持续存在的潜伏感染细胞库 采用高效抗逆转录病毒治疗（ART）。这些潜伏感染细胞的激活可以导致 在没有抗逆转录病毒治疗的情况下艾滋病毒反弹。在临床试验中，艾滋病毒表现出截然不同的动态 ART 停止后。大多数人体内的艾滋病病毒会迅速反弹，而只有一小部分人会迅速反弹。 个人，实现了长期的艾滋病毒缓解或治疗后控制（PTC）。尽管 尽管深入研究，我们对病毒控制的决定因素缺乏清晰和连贯的理解 或 ART 后 HIV 缓解的持续时间，这阻碍了有效治疗方法的开发 实现“功能性”治疗并最终实现灭菌治疗的策略。 这笔赠款弥补了这一知识空白。我们的中心假设是 PTC 不仅仅受驱动 由单一因素影响；相反，它是复杂的非线性相互作用中出现的现象 免疫反应和潜在储存库之间的关系，包括复制能力 水库和有缺陷的水库。理解这种动态相互作用将是关键 制定有效的干预措施以获得良好的临床结果。我们首先会划定 这些相互作用在通过整合最近的生物学知识来确定病毒控制中的作用 将研究结果转化为机械数学模型。我们将使用临床数据验证该模型 从后处理控制器和非控制器中，将估计的模型参数与 测量生物和免疫学标记物，以确定预测的患者特征 PTC。此外，我们将估计下一代药物的作用方式并量化其功效 潜伏期逆转剂 (LRA)、AZD5582 和一类有前途的基于双特异性抗体的药物 免疫治疗，双重亲和力重新靶向分子。最后，我们将整合模型 这些药物如何与潜在储存库与免疫相互作用的模型一起工作 评估和预测 LRA 和免疫治疗组合的影响的系统 储库和临床结果。 总而言之，我们的工作将为 1）理解艾滋病毒控制和 ART 后的反弹动态，2) 识别可能实现 PTC 的患者，3) 估计/预测治疗干预措施的影响，例如 LRA 和/或 免疫治疗，4）建议有效的干预措施以实现“功能性”治愈 根据患者特点。