An immune-based approach for HIV eradication

基于免疫的艾滋病毒根除方法

• 批准号: 9223640
• 负责人: JUAN LAMA
• 金额: $ 66.56万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223640
• 关键词: Adverse effects; Affect; Agonist; Anti-Retroviral Agents; Antibodies; Appearance; Autologous; Award; Biochemical; Biological Assay; CD4 Lymphocyte Count; CD8B1 gene; Cells; Cessation of life; Chemicals; Chimeric Proteins; Chronic Disease; Data; 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; Lead; Life; Mediating; Metabolic; Modeling; Mus; Nucleic Acids; Oral; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; 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 Latency; Virus Replication; antiretroviral therapy; 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; preclinical development; prevent; programs; public health relevance; purge; reactivation from latency; response; small molecule; small molecule inhibitor; social; social stigma; success; therapeutic vaccine; viral rebound

 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）：病毒储库根除已成为HIV研究领域的主要课题。有26种抗逆转录病毒药物（ARV）可用于有效治疗感染。艾滋病毒感染者已成为一种慢性疾病，其中90%以上的患者的病毒载量可以得到控制。然而，这种疾病的健康、社会和经济负担是前所未有的。社会耻辱、长期治疗期间积累的严重副作用以及卫生系统的巨大成本（估计患者一生中花费近50万美元）突出表明需要治愈艾滋病毒。在感染过程的早期，病毒潜伏在静止细胞内，并保持在不表达蛋白质或核酸的状态，也不产生新的病毒颗粒。这种潜伏感染细胞的储存库现在被视为艾滋病毒根除的主要障碍。即使存在有效的cART，也需要超过60年的时间才能完全消除水库，并且需要替代方法来治愈HIV。未来根除艾滋病毒的努力可能基于所谓的“休克和杀死”方法，即首先用“潜伏逆转剂”（LRA）将病毒从其潜伏的储库中重新激活，第二种疗法消除重新激活的细胞。用自体病毒进行的离体HIV再活化测定最近已经证明在生理环境中不能消除再活化的细胞。几个因素可以解释对CTL介导的杀伤的部分抗性，并且还防止通常由病毒CPE诱导的死亡。这些因素包括病毒抗原在再活化细胞中的低水平表达和HIV的内在特性，这些特性允许病毒逃避CTL免疫应答。在这个II期计划中，我们提出了一种基于HIV特异性免疫的方法，以促进对感染细胞的杀伤。在之前的I期研究中，我们成功鉴定了Nef介导的MHC-I下调的小分子抑制剂。我们表征了在HIV感染细胞中特异性阻断MHC-I下调的分子，而不干扰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。这些抑制剂防止具有低水平sMHC-I的感染细胞的出现，所述低水平的sMHC-I不能有效地呈递病毒抗原并且对CTL杀伤具有部分抗性。我们建议使用这些抑制剂来克服Nef的活性，并在用LRA药理学重新激活后促进潜伏感染细胞的增殖。通过药物化学优化抑制剂并确定临床前候选药物的具体目标如下所示：具体目标1。MHC-I下调抑制剂的先导优化。两个先导系列将进行多次迭代循环的先导优化，以提高效价， 特异性、代谢稳定性、溶解度、渗透性和生物相容性，目的是鉴定临床前候选物。具体目标2。通过体外、离体和体内试验验证高级候选物。一个先导系列中的高级分子将被用来测试它们在将CTL加入HIV复制细胞后的效果。还将使用体内模型评价抑制剂 的HIV潜伏期（人源化BLT小鼠），以确定它们是否减少了病毒库的大小和LRA治疗后病毒反弹的频率。具体目标3。初步确定作案手法。将进行旨在了解这些抑制剂作用机制的研究。将询问与宿主伴侣的假定相互作用，并进一步研究可被MHC-I抑制剂特异性阻断的相互作用。该II期申请的成功将定义为在大鼠中具有足够PK特性的临床前候选药物的里程碑识别，可预测人类经口给药。临床前候选物将在使用病毒血症患者样品和人源化BLT小鼠潜伏期模型的离体测定中得到验证。这些研究可能会导致一个新的家族的特异性免疫激活剂用于艾滋病毒根除方法的一流的抑制剂。