An immune-based approach for HIV eradication

基于免疫的艾滋病毒根除方法

• 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
• 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

 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（由适用提供）：消除病毒储层已成为艾滋病毒研究领域的主要主题。可以有效治疗感染，多种26个抗逆转录病毒（ARV）。患有艾滋病毒的人已成为一种慢性疾病，在该疾病中，可以在百分之九十的患者中控制病毒负荷。然而，疾病的健康，社会和经济燃烧是前所未有的。社会污名，长期治疗过程中积累的严重副作用以及对卫生系统的巨大成本，估计在患者的一生中估计约为一百万美元，突出了需要治愈艾滋病毒的需求。在感染过程的早期，病毒在静息细胞内变得潜在，并保持在未表达蛋白质或核酸的状态，并且没有制成新的病毒颗粒。现在，这种潜伏细胞的这种储层被视为阻碍消除HIV的主要屏障。即使在有高效的购物车的情况下，也需要超过60年的时间才能完全消除储层，并且需要采用替代方法来治愈HIV。未来消除艾滋病毒的努力可能基于所谓的“冲击和杀伤”方法，在该方法中，该病毒首先是从其潜在储层中重新反应的，其潜在储层（LRAS）（LRAS），第二种疗法消除了重新激活的细胞。带有自体病毒的前病毒HIV重新激活测定最近表明无法消除物理环境中重新激活的细胞。几个因素可以解释对CTL介导的杀戮的部分抗性，还可以防止病毒CPE通常诱导的死亡。这些因素包括在重新激活细胞中病毒抗原的表达水平低以及HIV的内在特性，使病毒能够逃脱CTL免疫反应。在此II期计划中，我们提出了一种基于HIV的免疫方法，以促进受感染细胞的杀戮。在上一个阶段的奖励中，我们成功地鉴定了固定介导的MHC-I下调的小分子抑制剂。我们表征了分子，这些分子特异性地阻断了HIV感染细胞中MHC-I的下调，而不会干扰未感染的细胞中其表面水平，而不会影响其他无关的宿主蛋白。这些抑制剂防止了SMHC-I水平低的感染细胞的出现，SMHC-I无法有效地呈现病毒抗原，并且对CTL杀伤具有部分抗性。我们建议使用这些抑制剂克服NEF的活性，并促进用LRA进行药物重新激活后潜在感染细胞的杀伤。下面列出了通过医学化学来优化抑制剂并确定临床前候选者的具体目的：特定目标1。对MHC-I下调抑制剂的铅优化。两个铅系列将经过多个铅优化的迭代循环，以提高效力， 特异性，代谢稳定性，溶解度，渗透性和CYP概况，目的是识别临床前候选者。特定目的2。用体外，前体和体内测定的高级候选者的验证。在将CTL添加到HIV复制细胞中后，将使用一个铅系列中的晚期分子来测试其作用。抑制剂还将通过体内模型进行评估 HIV潜伏期（人源化BLT小鼠）的确定是否会减小病毒储存库的大小以及LRA治疗后病毒反弹的频率。特定目的3。M.O.A.的初步确定旨在了解这些抑制剂作用机理的研究将进行。将审问与主机伴侣的推定互动，并将进一步研究MHC-I抑制剂的特异性互动。在此II期应用中的成功将被定义为对大鼠具有足够PK特性的临床前候选者的里程碑识别，可以预测人类口服的使用。临床前候选者将在带有恶毒患者的样品以及人源化的BLT小鼠潜伏期模型中对临床前候选者进行验证。这些研究可能会导致一种新型特异性免疫激活剂家族的第一类抑制剂，用于消除HIV方法。