An immune-based approach for HIV eradication

基于免疫的艾滋病毒根除方法

基本信息

批准号：
9031713
负责人：
JUAN LAMA
金额：
$ 122.64万
依托单位：
RETROVIROX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9031713
关键词：
Adverse effects Affect Agonist Antibodies Appearance Autologous Award Biochemical Biological Assay CD4 Lymphocyte Count CD8B1 gene Cells Cessation of life Chemicals Chimeric Proteins Chronic Disease Data Development Down-Regulation Family Frequencies Funding Future Genetic Transcription Goals HIV HIV Infections Health Health system Human Immune Immune response Immune system In Vitro Infection Interphase Cell Interruption Latent Virus Lead Life Mediating Metabolic Modeling Mus Nucleic Acids Oral Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Physiological Preparation Principal Investigator Problem Solving Process Property Protein Kinase C Proteins Rattus Research Resistance Rodent Model Role Sampling Series Shock Small Business Innovation Research Grant Solubility Source Specificity Surface T-Cell Activation Testing Therapeutic Index Validation Viral Viral Antigens Viral Load result Viral reservoir Virus Virus Diseases Virus Replication base burden of illness cell killing cost humanized mouse improved in vitro Model in vitro testing in vivo in vivo Model inhibitor/antagonist killings lead series mouse model novel particle pre-clinical prevent programs purge response small molecule small molecule inhibitor social social stigma success therapeutic vaccine

项目摘要

DESCRIPTION (provided by applicant): Viral reservoir eradication has become a leading subject in the field of HIV research. A plethora of 26 antiretrovirals (ARVs) are available to efficiently treat infection. Living with HIV has become a chronic disease in which viral load can be controlled in over ninety percent of patients. Yet, the health, social, and economical burden of the disease are unprecedented. Social stigma, serious side effects accumulated during long-life treatments, and a tremendous cost to the health system, estimated at near half a million dollars throughout the life of a patient, highlight the need of a cure for HIV. Early in the courseof infection the virus becomes latent within resting cells and remains in a state in which no protein or nucleic acids are expressed, and no new viral particles are made. This reservoir of latentlyinfected cells is now seen as the primary barrier standing in the way of HIV eradication. Even in the presence of efficient cART, over 60 years are required to completely eliminate the reservoir, and alternative approaches to cure HIV are needed. Future efforts to eradicate HIV will likely be based on the so-called "shock and kill" approach, where the virus is first reactivatd from its latent reservoirs with "latency-reversing-agents" (LRAs), and a second therapy eliminates reactivated cells. Ex-vivo HIV reactivation assays with autologous virus have recently demonstrated the inability to eliminate reactivated cells in physiological settings. Several factor can explain the partial resistance to CTL-mediated killing, and also preventing death normally induced by the viral CPE. These factors include the low level of expression of viral antigens in reactivated cells and the intrinsic properties of HIV that allow the virus to escape the CTL immune response. In this Phase II program, we propose an HIV-specific immune-based approach to facilitate the killing of infected cells. In a previous Phase I award, we successfully identified small-molecule inhibitors of the Nefmediated MHC-I downmodulation. We characterized molecules that specifically block downmodulation of MHC-I in HIV infected cells without interfering with its surface levels in uninfected cells, and without affecting other unrelated host proteins. These inhibitors prevent the appearance of infected cells with low levels of sMHC-I, which cannot efficiently present viral antigens and are partially resistant to CTL killing. We propose to use these inhibitors to overcome the activity of Nef and facilitate the killng of latently infected cells after pharmacological reactivation with LRAs. The specific aims to optimize inhibitors through medicinal chemistry and identify a preclinical candidate are presented below: Specific Aim 1. Lead optimization of inhibitors of MHC-I downmodulation. Two lead series will be subjected to multiple iterative cycles of lead optimization to improve potency, specificity, metabolic stability, solubility, permeability and CYP profiles, with the goal to identfy a preclinical candidate. Specific Aim 2. Validation of advanced candidates with in vitro, ex-vivo and in vivo assays. Advanced molecules in one lead series will be used to test their effect after addition of CTLs to HIV replicating cells. Inhibitors will also be evaluated with and in-vivo model of HIV latency (humanized BLT mice) to determine whether they diminish the size of the viral reservoir and the frequency of viral rebound after LRA treatment. Specific Aim 3. Preliminary determination of m.o.a. Studies aimed at understanding the mechanism of action of these inhibitors will be carried out. Putative interactions with host partners will be interrogated and those that can be specifically blocked by the MHC-I inhibitors will be further investigated. Success in this Phase II application will be defined as the milestone identification of a preclinicl candidate with adequate PK properties in rats, predictive of oral use in humans. The preclinical candidate will have been validated in ex-vivo assays with samples of aviremic patients, and with the humanized BLT mouse model of latency. These studies may result in first-in-class inhibitors of a novel family of specific immune activators for use in HIV eradication approaches.

描述（由申请人提供）：消灭病毒库已成为 HIV 研究领域的一个前沿课题。有 26 种抗逆转录病毒药物 (ARV) 可有效治疗 HIV 感染已成为一种慢性疾病。然而，该疾病给百分之九十以上的患者带来了前所未有的健康、社会和经济负担，社会耻辱、长期治疗过程中积累的严重副作用以及巨大的健康成本。该系统预计在患者一生中花费近50万美元，这凸显了治愈艾滋病毒的必要性，在感染过程的早期，病毒会潜伏在静止细胞中，并保持在没有蛋白质或核酸的状态。表达，并且没有产生新的病毒颗粒，这种潜伏感染细胞的储存库现在被视为阻碍 HIV 根除的主要障碍，即使存在有效的 cART，也需要 60 多年才能完全消除该储存库。以及替代治疗方法未来消除艾滋病毒的努力可能会基于所谓的“休克和杀灭”方法，即首先使用“潜伏期逆转剂”（LRAs）将病毒从其潜伏库中重新激活，然后再进行第二次激活。最近，用自体病毒进行的体外 HIV 重新激活试验表明，在生理环境中无法消除重新激活的细胞，有几个因素可以解释对 CTL 介导的杀伤的部分抵抗，并阻止这种现象的发生。通常由病毒 CPE 诱导的死亡。这些因素包括重新激活的细胞中病毒抗原的低水平表达以及 HIV 的固有特性，这些特性使病毒能够逃避 CTL 免疫反应。在这个第二阶段计划中，我们提出了一种 HIV-在之前的 I 期奖项中，我们成功鉴定了 Nef 介导的 MHC-I 下调的小分子抑制剂，这些分子能够特异性阻断 HIV 感染细胞中 MHC-I 的下调。不干涉其在未感染细胞中的表面水平，并且不影响其他不相关的宿主蛋白，这些抑制剂可防止低水平 sMHC-I 的感染细胞的出现，这些细胞不能有效地呈递病毒抗原，并且对 CTL 杀伤具有部分抵抗力。这些抑制剂可克服 Nef 的活性，并促进 LRA 药理学重新激活后杀死潜伏感染的细胞。具体目标是通过药物化学优化抑制剂并确定临床前候选药物：具体目标。目标 1. MHC-I 下调抑制剂的先导化合物优化。两个先导化合物系列将经历先导化合物优化的多个迭代循环，以提高效力，特异性、代谢稳定性、溶解度、渗透性和 CYP 谱，旨在确定临床前候选药物。具体目标 2. 将在一个先导系列中使用先进的分子进行体外、离体和体内验证。还将使用体内模型来评估向 HIV 复制细胞添加 CTL 后的效果。 HIV 潜伏期（人源化 BLT 小鼠），以确定 LRA 治疗后病毒库的大小和病毒反弹的频率是否会减少。具体目标 3. 旨在了解这些抑制剂作用机制的初步测定。与宿主伙伴的假定相互作用将受到质疑，并且将进一步研究可被 MHC-I 抑制剂特异性阻断的相互作用，这一 II 期应用的成功将被定义为临床前的里程碑鉴定。候选药物在大鼠中具有足够的 PK 特性，可预测人类口服使用。临床前候选药物将在无病毒血症患者样本和人源化 BLT 小鼠潜伏期模型中得到验证。新型特异性免疫激活剂家族的类内抑制剂，用于根除艾滋病毒的方法。