Intervening with Latent HIV-1 Infection using Gnidimacrin

使用 Gnidimacrin 干预潜伏性 HIV-1 感染

• 批准号: 8658778
• 负责人: Chin-Ho Chen
• 金额: $ 23.55万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658778
• 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; 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; public health relevance; purge; response; success

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 toxic 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 effect 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.

虽然抗逆转录病毒疗法（ART）已成功地控制了HIV-1阳性患者的病毒复制， 艾滋病毒-1被抑制而不是根除。据信，潜伏的HIV-1储存库是 导致了持续感染因此，从潜伏宿主中消除HIV-1的策略是 需要治愈/功能性治愈持续性HIV-1感染。我们的长期目标是发展一个有选择性的 蛋白激酶C激动剂gnidimacrin（GM）作为HIV-1根除的辅助治疗剂。全球机制是一个 在皮摩尔浓度下激活潜伏的HIV-1复制的异常有效的天然产物。不 对未感染的细胞有毒，直到达到微摩尔浓度。GM至少比 组蛋白去乙酰化酶抑制剂伏立诺他（SAHA）是研究最充分的HIV-1潜伏激活剂。更重要的是， 在潜伏感染的细胞系模型中，GM诱导的病毒产量大约是SAHA的10倍。 虽然SAHA被证明可以破坏HIV-1的潜伏期，但它似乎对减少潜伏的HIV无效。 通过潜伏病毒激活后的自体CTL反应或细胞病变效应来抑制储库。因此， 提出可能需要其他策略，如CTL激活，以消除潜伏感染的细胞 SAHA治疗后。由于GM在潜伏病毒激活方面比SAHA强得多，我们假设 转基因的强烈激活将导致HIV-1潜伏感染细胞产生强大的HIV-1， 使潜伏感染的细胞对活化的潜伏感染的CTL应答和/或细胞病变效应敏感， 病毒因此，本研究的目的是确定GM对减少潜伏病毒储库的影响 使用来自HIV-1阳性患者的原代PBMC，并建立关键的药理学和毒理学 这是未来体内临床前研究所需的特征。这些目标将通过以下方式实现 具体目的：1）确定GM在减少初级静息CD 4+细胞中HIV-1储库方面的有效性 患者的细胞。我们实现这一目标的方法是确定潜在的易感性 感染的CD 4细胞对CTL应答和GM激活的潜伏病毒的致细胞病变作用; 2）建立 GM的临床前药代动力学和毒理学特征。由于PKC属于丝氨酸/苏氨酸蛋白家族， 激酶参与重要的细胞功能，这是至关重要的，以确定临床前药理学和 在体内动物研究之前，对GM的毒理学特性进行评估，以确定其功效。小动物模型将用于 建立GM的药代动力学和毒理学特征。除了其强大的抗潜伏期活动，GM 也具有优于HDAC抑制剂的优点，因为它在pM抑制HIV-1 R5病毒的再感染 浓度的拟议的研究将使我们能够确定转基因是否可以减少/消除潜在的 感染静息CD 4细胞而不进行额外的免疫干预。因此，GM有潜力成为 有吸引力的HIV-1根除候选药物。