Nonhuman Primate Model for Eradication Therapy

高效抗逆转录病毒疗法（HAART），包括抗逆转录病毒药物的有效组合，是治疗HIV-1感染和艾滋病的一个重大进展。然而，这些方案不能根除可能建立潜伏期的病毒。一种建议的根除方法涉及从潜伏宿主中诱导病毒，同时继续H/ART。 治疗方法可抑制病毒从水塘释出的扩散。这种方法，称为诱导/根除疗法，是基于激活病毒基因表达的药物。我们正在使用一种非人灵长类动物模型（RT-SHIV），该模型概括了人类HIV-1感染的许多特征，包括H/ART对病毒载量的抑制。重要的是，该模型通过测量HAART和病毒激活剂治疗停止后的病毒反弹，能够严格评估治疗方案的潜在临床影响。假设在HAART下，RT-SHIV感染的猕猴中潜伏病毒的药理学诱导将消除病毒或显著降低病毒水平，从而产生无药物缓解。我们将首先关注suborylanilide hydroxamic acid（SAHA，伏立诺他），一种组蛋白去乙酰化酶（HDAC）抑制剂，它影响细胞中的染色质重塑。 病毒启动子HDAC抑制剂和特异性转录途径的小分子激活剂之间的协同效应已用于在HIV潜伏期的细胞培养模型中诱导病毒。因此，我们将掺入其他病毒诱导剂（例如，苔藓抑素-蛋白激酶C和NF-kB途径的激活剂），以确定最佳诱导疗法是否应涉及通过调节病毒转录的不同机制起作用的诱导剂的组合。目的1：在RTSHIV/猕猴模型中测试基于强化HAART和SAHA加苔藓抑素的诱导/根除疗法。目的2：在猕猴模型中分析诱导/根除治疗的机制。目的3：测试新的病毒诱导化合物和艾滋病毒合作实验室确定的方法。目的4：评价猕猴感染RT-SHIV后早期联合HAART诱导治疗的有效性。

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.