Intervening with Latent HIV-1 Infection using Gnidimacrin

使用 Gnidimacrin 干预潜伏性 HIV-1 感染

• 批准号: 8828549
• 负责人: Chin-Ho Chen
• 金额: $ 19.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828549
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Adjuvant; Agonist; Animal Model; Animals; Anti-Retroviral Agents; Autologous; Biological Factors; CD4 Positive T Lymphocytes; Cell Line; Cell physiology; Cells; Country; Drug Kinetics; Effectiveness; Excretory function; Family; Future; Goals; HIV; HIV-1; Health; Histone Deacetylase Inhibitor; Individual; Infection; Latent Virus; Metabolism; Modeling; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Predisposition; Production; Property; Protein Kinase C; Protein-Serine-Threonine Kinases; Public Health; Rest; Therapeutic; Toxic effect; Toxicology; Tumor Promotion; Viral; Viral Cytopathogenic Effect; Virus; Virus Replication; Vorinostat; absorption; cancer cell; drug candidate; drug development; gnidimacrin; immune activation; immune clearance; immunological intervention; in vivo; latent infection; latent virus activation; pandemic disease; pre-clinical; preclinical study; prostratin; purge; response; success

DESCRIPTION: While anti-retroviral therapy (ART) has been successful in controlling virus replication in HIV-1 positive individuals, HIV-1 is suppressed rather than eradicated. It is believed that latent HIV-1 reservoirs are responsible for the persistent infection. Therefore, strategies that eliminate HIV-1 from latent reservoirs are needed to cure/functionally cure persistent HIV-1 infection. Our long term goal is to develop a selective protein kinase C agonist gnidimacrin (GM) as an adjuvant therapeutic for HIV-1 eradication. GM is an unusually potent natural product that activates latent HIV-1 replication at picomolar concentrations. It is not toxi to uninfected cells until it reaches micromolar concentrations. GM is at least 4 log10 more potent than the most well studied histone deacetylase inhibitor vorinostat (SAHA) for latent HIV-1 activation. More importantly, GM induces approximately 10-fold more virus production than SAHA in a latently infected cell line model. Although SAHA was shown to disrupt HIV-1 latency, it appears to be ineffective in reducing latent HIV reservoirs through autologous CTL responses or cytopathic effect following latent viral activation. Thus, it was proposed that other strategies such as CTL activation, might be needed to eliminate latently infected cells following SAHA treatment. Since GM is much stronger than SAHA in latent virus activation, we hypothesize that strong activation by GM will result in robust HIV-1 production from HIV-1 latently infected cells, which will render the latently infected cells susceptible to CTL responses and/or cytopathic effects of the activated latent viruses. Therefore, the goal of this study is to determine the effet of GM on reducing latent viral reservoirs using primary PBMCs from HIV-1 positive patients, and to establish crucial pharmacology and toxicology profiles that are needed for future in vivo pre-clinical studies. The goals will be achieved with the following Specific Aims: 1) determining the effectiveness of GM on reducing HIV-1 reservoirs in primary resting CD4 cells from patients. Our approaches to accomplish this aim are to determine the susceptibility of latently infected CD4 cells to CTL responses and cytopathic effects of GM-activated latent viruses; 2) establishing the preclinical pharmacokinetic and toxicology profiles of GM. Since PKC belongs to a family of serine/threonine kinases involved in vital cellular functions, it is essential to determine the preclinical pharmacological and toxicological properties of GM before in vivo animal studies for efficacy. Small animal models will be used to establish the pharmacokinetic and toxicology profiles of GM. In addition to its strong anti-latency activity, GM also has advantage over HDAC inhibitors in that it inhibits re-infection of HIV-1 R5 viruses at pM concentrations. The proposed study will allow us to determine whether GM can reduce/eliminate latently infected resting CD4 cells without additional immunological interventions. Thus GM has the potential to be an attractive drug candidate for HIV-1 eradication.

描述：虽然抗逆转录病毒治疗（ART）已经成功地控制了HIV-1阳性个体的病毒复制，但HIV-1是被抑制的，而不是被根除的。人们认为潜伏的HIV-1宿主是造成持续感染的原因。因此，需要从潜伏宿主中消除HIV-1的策略来治愈/功能性治愈持续性HIV-1感染。我们的长期目标是开发一种选择性蛋白激酶C激动剂gnidimacrin （GM）作为根除HIV-1的辅助治疗。转基因是一种异常有效的天然产物，可以激活潜伏的HIV-1在皮摩尔浓度下的复制。在达到微摩尔浓度之前，它对未感染的细胞不具有毒性。GM对HIV-1潜伏激活的效力至少比研究最充分的组蛋白去乙酰化酶抑制剂伏立诺他（SAHA）强4 log10。更重要的是，在潜伏感染的细胞系模型中，转基因诱导的病毒产量大约是SAHA的10倍。尽管SAHA被证明可以破坏HIV-1潜伏期，但它似乎不能通过自身CTL反应或潜伏病毒激活后的细胞病变效应来减少潜伏的HIV储存库。因此，有人提出可能需要其他策略，如CTL激活，来消除SAHA治疗后的潜伏感染细胞。由于GM在潜伏病毒激活方面比SAHA强得多，我们假设GM的强激活将导致HIV-1潜伏感染的细胞产生强大的HIV-1，这将使潜伏感染的细胞对活化的潜伏病毒的CTL反应和/或细胞病变作用敏感。因此，本研究的目的是利用HIV-1阳性患者的原代pbmc来确定转基因对减少潜伏病毒库的影响，并为未来的体内临床前研究建立关键的药理学和毒理学资料。目标将通过以下具体目标来实现：1)确定转基因对减少患者原发静息CD4细胞中HIV-1储库的有效性。我们实现这一目标的方法是确定潜伏感染的CD4细胞对CTL反应的敏感性和转基因激活的潜伏病毒的细胞病变效应；2)建立GM的临床前药代动力学和毒理学特征。由于PKC属于参与重要细胞功能的丝氨酸/苏氨酸激酶家族，因此在进行体内动物实验前确定GM的临床前药理学和毒理学特性至关重要。小动物模型将用于建立GM的药代动力学和毒理学分析。除了其强大的抗潜伏期活性外，GM还具有比HDAC抑制剂更强的优势，因为它可以在pM浓度下抑制HIV-1 R5病毒的再感染。拟议的研究将使我们能够确定转基因是否可以减少/消除潜伏感染的静息CD4细胞，而无需额外的免疫干预。因此，转基因有可能成为一种有吸引力的根除HIV-1的候选药物。