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）已成功控制HIV-1阳性病毒复制 个人，HIV-1被抑制而不是根除。据信潜在的HIV-1储层是 负责持续感染。因此，从潜在水库中消除HIV-1的策略是 需要治愈/在功能上治愈持续的HIV-1感染。我们的长期目标是发展一个选择性 蛋白激酶C激动剂GNIDIMACRIN（GM）作为消除HIV-1的辅助治疗。通用汽车是一个 异常有效的天然产物在皮摩尔浓度下激活潜在的HIV-1复制。它不是 对未感染的细胞有毒，直到达到微摩尔浓度。 GM至少4 log10的效力比 大多数研究的组蛋白脱乙酰基酶抑制剂伏立替纳斯塔特（SAHA）用于潜在的HIV-1激活。更重要的是， 在潜在感染的细胞系模型中，GM诱导的病毒产生大约比SAHA多10倍。 尽管SAHA被证明破坏了HIV-1潜伏期，但在减少潜在艾滋病毒方面似乎是无效的 潜在病毒激活后，通过自体CTL反应或细胞病变作用的储层。因此，是 提出可能需要其他策略（例如CTL激活）来消除潜在感染的细胞 经过Saha治疗。由于GM在潜在病毒激活中比SAHA强得多，因此我们假设 通用汽车的强大激活将导致HIV-1受感染细胞的强劲HIV-1产生，这将会 使受激活潜伏的CTL反应和/或细胞病变敏感的潜在感染细胞对活化潜伏 病毒。因此，这项研究的目的是确定GM对减少潜在病毒储存的影响 使用来自HIV-1阳性患者的主要PBMC，并建立关键的药理学和毒理学 未来体内临床前研究所需的曲线。目标将实现以下 具体目的：1）确定GM对降低主要静止CD4中HIV-1储层的有效性 来自患者的细胞。我们实现此目标的方法是确定潜在的敏感性 感染了转基因活化潜在病毒的CTL反应和细胞病变作用； 2）建立 GM的临床前药代动力学和毒理学谱。由于PKC属于丝氨酸/苏氨酸家族 参与重要细胞功能的激酶，必须确定临床前药理和 在体内动物研究之前，通用汽车的毒理学特性以提高功效。小动物模型将用于 建立GM的药代动力学和毒理学概况。除了其强大的抗延迟活性外，GM 比HDAC抑制剂具有优势，因为它抑制了PM的HIV-1 R5病毒的再感染 浓度。拟议的研究将使我们能够确定转基因是否可以减少/消除 未经其他免疫干预措施感染了静息CD4细胞。因此，通用汽车有可能成为 消除HIV-1的有吸引力的药物。