Primate Model Towards HIV Eradication Strategies

灵长类动物模型走向艾滋病毒根除策略

• 批准号: 8292211
• 负责人: THOMAS W NORTH
• 金额: $ 70.59万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292211
• 关键词: Animal Model; Anti-Retroviral Agents; Antiviral Agents; Antiviral Therapy; Biological Assay; Blood; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Clinical; DNA; Detection; Development; Drug Combinations; Future; Goals; HIV; HIV-1; Health; Highly Active Antiretroviral Therapy; Human; Individual; Infection; Integrase Inhibitors; Latent Virus; Liquid substance; Macaca; Macaca mulatta; Measures; Modeling; Monitor; Organ; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Population; Primates; Protease Inhibitor; RNA; RNA-Directed DNA Polymerase; Regimen; Relative (related person); Research; Residual state; Rest; Reverse Transcriptase Polymerase Chain Reaction; SIV; Sampling; T memory cell; T-Lymphocyte; Time; Tissues; Transcript; Treatment Protocols; Viral; Viral Genome; Viral load measurement; Viremia; Virus; Virus Latency; Virus Replication; analog; antiretroviral therapy; cell type; design; efavirenz; efficacy evaluation; improved; insight; macrophage; monocyte; non-nucleoside reverse transcriptase inhibitors; novel; nucleoside analog; pinacolyl methylphosphonic acid; prevent; simian human immunodeficiency virus; success; viral DNA; viral RNA

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop and evaluate strategies for eradication of HIV-1 from infected individuals. These studies will be performed with an animal model that enables comprehensive analyses of viral reservoirs and replication dynamics during HAART. This model utilizes rhesus macaques infected by a chimeric virus of SIVmac239 containing the HIV-1 reverse transcriptase (RT) in place of the SIV RT (RT-SHIV). In this model a three-drug combination that is widely used in humans [efavirenz + (-)-FTC + PMPA] mimics HAART in HIV- 1-infected humans with respect to virus load (VL) suppression and rebound upon cessation of drug therapy. In order to study eradication strategies in the RT-SHIV/macaque model, we have developed a sensitive VL assay with a limit of detection of 1-2 copies of viral RNA (vRNA) per ml of plasma, and have also developed sensitive RT-PCR and PCR assays to measure vRNA and viral DNA (vDNA) in tissues. The goal of this project is to evaluate enhanced HAART in combinations that may more fully suppress plasma and tissue VLs to levels below detection with our sensitive PCR assays. Because a potential limitation of current antiretroviral therapy is access of drugs to key reservoir tissues, we will also determine levels of drugs in target tissues and use that information to optimize drug regimens. In addition to virological endpoints, the impact of these drug combinations will be evaluated in RT-SHIV-infected resting CD4+ lymphocyte populations. Importantly, the highly manipulatable RT-SHIV/macaque model enables assessment of potential clinical impact by determining effects on delay or reduction of viral rebound upon cessation of therapy. The drug combinations we propose are designed to evaluate: i) optimization of DNA chain termination with combinations of four potent nucleoside analogs (NRTI) in combination with efavirenz (NNRTI) or an integrase inhibitor, raltegravir; ii) combinations of the most effective NRTIs with both efavirenz and raltegravir; and iii) enhancement of the most potent drug combination with a protease inhibitor or a CCR5 antagonist. The overall Hypothesis of this project is that an intensified HAART regimen has the potential to eliminate RT-SHIV from infected macaques. These studies will provide insight on the requirements for complete suppression of virus replication in tissues and specific cell types as well as in plasma. Thus, this project aims to determine whether there is a limitation to suppression of residual viremia with antiviral drug combinations and whether eradication will also require "induction" strategies for reactivation of latent virus. PUBLIC HEALTH RELEVANCE: It is likely that eradication of HIV-1 from infected individuals will require both full suppression of virus replication and the reactivation of latent virus during fully suppressive therapy. The focus of this project is elimination of residual virus replication in cells and tissues. The results will provide important information about the relative contributions of virus replication and other reactivation of latent virus to residual viremia during HAART, the relationship between drug levels and virus suppression in tissues and specific cell types, and the effect of enhanced therapy on latent reservoirs in resting CD4+ T lymphocytes. The results of this study will also contribute to future studies of strategies for eliminate the resting memory T cell reservoir of latent HIV-1. The success of such induction strategies will likely be dependent on the ability of fully suppressive HAART to prevent replication of reactivated virus.

描述（由申请人提供）：该项目的长期目标是制定和评估从感染者身上根除 HIV-1 的策略。这些研究将使用动物模型进行，该模型能够在 HAART 期间全面分析病毒库和复制动态。该模型利用被 SIVmac239 嵌合病毒感染的恒河猴，该病毒含有 HIV-1 逆转录酶 (RT) 代替 SIV RT (RT-SHIV)。在该模型中，广泛用于人类的三药组合[依非韦伦 + (-)-FTC + PMPA] 在病毒载量 (VL) 抑制和停止药物治疗后反弹方面模拟 HIV-1 感染者的 HAART 。为了研究 RT-SHIV/猕猴模型中的根除策略，我们开发了一种灵敏的 VL 检测方法，检测限为每毫升血浆 1-2 个拷贝的病毒 RNA (vRNA)，并且还开发了灵敏的 RT-SHIV 检测方法。用于测量组织中 vRNA 和病毒 DNA (vDNA) 的 PCR 和 PCR 测定。该项目的目标是评估增强型 HAART 的组合，这些组合可以更充分地将血浆和组织 VL 抑制至低于我们灵敏的 PCR 检测检测到的水平。由于当前抗逆转录病毒治疗的一个潜在限制是药物进入关键储存组织，因此我们还将确定靶组织中的药物水平，并利用该信息来优化药物治疗方案。除了病毒学终点之外，还将在感染 RT-SHIV 的静息 CD4+ 淋巴细胞群中评估这些药物组合的影响。重要的是，高度可操作的 RT-SHIV/猕猴模型可以通过确定停止治疗后延迟或减少病毒反弹的效果来评估潜在的临床影响。我们提出的药物组合旨在评估： i) 四种有效核苷类似物 (NRTI) 与依非韦伦 (NNRTI) 或整合酶抑制剂拉替拉韦 (raltegravir) 组合的 DNA 链终止优化； ii) 最有效的 NRTI 与依非韦伦和拉替拉韦的组合； iii) 增强与蛋白酶抑制剂或 CCR5 拮抗剂的最有效药物组合。该项目的总体假设是强化HAART疗法有可能消除受感染猕猴体内的RT-SHIV。这些研究将深入了解完全抑制病毒在组织和特定细胞类型以及血浆中复制的要求。因此，该项目旨在确定抗病毒药物组合对抑制残留病毒血症是否存在限制，以及根除病毒是否还需要“诱导”策略来重新激活潜伏病毒。公共卫生相关性：从感染者身上根除 HIV-1 可能需要在完全抑制治疗期间完全抑制病毒复制并重新激活潜伏病毒。该项目的重点是消除细胞和组织中残留的病毒复制。结果将提供重要信息，包括HAART期间病毒复制和其他潜伏病毒再激活对残留病毒血症的相对贡献、组织和特定细胞类型中药物水平与病毒抑制之间的关系，以及强化治疗对潜伏病毒库的影响。静息 CD4+ T 淋巴细胞。这项研究的结果也将有助于未来研究消除潜伏 HIV-1 静息记忆 T 细胞库的策略。这种诱导策略的成功可能取决于完全抑制性HAART阻止病毒复制的能力。

项目成果

Cellular pharmacology and potency of HIV-1 nucleoside analogs in primary human macrophages.

原代人巨噬细胞中 HIV-1 核苷类似物的细胞药理学和效力。

• 发表时间: 2013-03
• 影响因子: 4.9
• 作者: Gavegnano, Christina;Detorio, Mervi A;Bassit, Leda;Hurwitz, Selwyn J;North, Thomas W;Schinazi, Raymond F
• 通讯作者: Schinazi, Raymond F

Synthesis of 7-trifluoromethyl-7-deazapurine ribonucleoside analogs and their monophosphate prodrugs.

7-三氟甲基-7-脱氮嘌呤核糖核苷类似物及其单磷酸酯前药的合成。

• 发表时间: 2020
• 作者: Cho, Jong Hyun;Bassit, Leda C;Amblard, Franck;Schinazi, Raymond F
• 通讯作者: Schinazi, Raymond F