Nonhuman Primate Model for Eradication Therapy

用于根除治疗的非人类灵长类动物模型

• 批准号: 8377513
• 负责人: Paul Luciw
• 金额: $ 42.42万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8377513
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Antiviral Agents; Autopsy; Cell Culture Techniques; Cells; Chronic; Chronic Phase; Clinical; Complex; Disease remission; Dissection; Evaluation; Gene Expression; Genetic Transcription; HIV; HIV-1; Highly Active Antiretroviral Therapy; Histone Acetylation; Histone Deacetylase Inhibitor; Human; Hydroxamic Acids; Immune response; Infection; Instruction; Kinetics; Latent Virus; Life; Lymphoid Cell; Macaca; Macaca mulatta; Measurement; Measures; Mediating; Methods; Modeling; Molecular; Monitor; Mus; NF-kappa B; Neoadjuvant Therapy; Organ; Participant; Pathway interactions; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Plasma; Play; Positive Transcriptional Elongation Factor B; Protein Kinase C; Proviruses; RNA-Directed DNA Polymerase; Regimen; Residual state; SIV; Satellite Viruses; Staging; Testing; Tissues; Transcript; Treatment Protocols; Viral; Viral Antigens; Viral Genes; Viral load measurement; Viremia; Virus; Virus Activation; Virus Diseases; Virus Latency; Vorinostat; Withholding Treatment; base; bryostatin; chromatin remodeling; collaboratory; cytotoxic; in vivo; latent virus activation; lymph nodes; multidisciplinary; nonhuman primate; novel; novel therapeutic intervention; programs; promoter; purge; simian human immunodeficiency virus; small molecule; transcription factor; viral DNA; viral RNA

Highly active antiretroviral therapy (HAART), consisting of potent combinations of antiretroviral drugs, has been a major advance in the treatment of HIV-1 infection and AIDS. However, these regimens do not eradicate the virus which can establish latency. A proposed approach for eradication involves induction of the virus from latent reservoirs while continuing H/\ART. Simultaneous HAART during this induction treatment would inhibit the spread of virus released from reservoirs. This approach, designated induction/eradication therapy, is based on agents that activate viral gene expression. We are using a nonhuman primate model (RT-SHIV) that recapitulates many of the features of HIV-1 infection in humans, including suppression of virus load by H/\ART. Importantly, this model enables rigorous assessment of the potential clinical impact of treatment regimens by allowing measurement of viral rebound upon cessation of treatment with both HAART and viral activators. The hypothesis is that pharmacologic induction of latent virus in RT-SHIV infected macaques under HAART will either eliminate virus or substantially reduce levels of virus and thereby produce a drug-free remission. We will first focus on suborylanilide hydroxamic acid (SAHA, Vorinostat), a histone deacetylase (HDAC) inhibitor which influences chromatin remodeling atthe viral promoter. Synergistic effects between HDAC inhibitors and small molecule activators of specific transcription pathways have been used for induction of virus in cell culture models of HIV latency. Accordingly, we will incorporate other viral inducers (e.g., bryostatin - an activator of protein kinase C and the NF-kB pathway) to determine whether an optimal induction therapy should involve a combination of inducers that act through different mechanisms regulating viral transcription. Aim 1: To test an induction/eradication therapy based on intensified-HAART and SAHA plus bryostatin in the RTSHlV/ macaque model. Aim 2: To analyze the mechanism(s) of induction/eradication therapy in the macaque model. Aim 3: To test novel viral induction compounds and approaches identified in the HIV Collaboratory. Aim 4: To evaluate the efficacy of an induction regimen given together with HAART very early after RT-SHIV infection of macaques.

高效抗逆转录病毒疗法(HAART)由多种有效的抗逆转录病毒药物组合而成，是治疗HIV-1感染和艾滋病的重大进展。然而，这些疗法并不能根除可能造成潜伏期的病毒。一种拟议的根除方法包括从潜伏的宿主中诱导病毒，同时继续H/\ART。诱导过程中的同步HAART 治疗将抑制从水库释放的病毒的传播。这种方法被称为诱导/根除疗法，其基础是激活病毒基因表达的制剂。我们正在使用一个非人类灵长类动物模型(RT-SHIV)，它概括了人类感染HIV-1的许多特征，包括通过H/\ART抑制病毒载量。重要的是，该模型允许在停止使用HAART和病毒激活剂治疗时测量病毒反弹，从而能够严格评估治疗方案的潜在临床影响。假设在HAART下对RT-SHV感染的猕猴进行潜伏病毒的药物诱导可以消除病毒或显著降低病毒水平，从而产生非药物缓解。我们将首先关注亚甲基苯胺异羟肟酸(SAHA，Vorinostat)，这是一种组蛋白去乙酰化酶(HDAC)抑制剂，它影响染色质重塑。 病毒推动者。HDAC抑制剂和特定转录途径的小分子激活剂之间的协同效应已被用于在HIV潜伏的细胞培养模型中诱导病毒。因此，我们将结合其他病毒诱导剂(例如，蛋白激酶C的激活剂bryostatin和核因子-kB途径)来确定最佳的诱导疗法是否应该包括通过不同机制调节病毒转录的诱导剂的组合。目的1：在RTSHlV/猕猴模型中测试基于强化HAART和SAHA+bryostatin的诱导/根除疗法。目的：分析猕猴模型诱导/根除治疗的作用机制(S)。目的3：测试HIV合作实验室中发现的新的病毒诱导化合物和方法。目的：评价RT-SHV感染猕猴后早期给予诱导方案和HAART的疗效。