PRIMATE MODEL TOWARDS HIV ERADICATION STRATEGIES

灵长类动物模型实现艾滋病毒根除策略

• 批准号: 8172619
• 负责人: THOMAS W NORTH
• 金额: $ 11.41万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172619
• 关键词: Animal Model; Antiviral Agents; Biological Assay; CCR5 gene; CD4 Positive T Lymphocytes; Clinical; Computer Retrieval of Information on Scientific Projects Database; DNA; Detection; Drug Combinations; Funding; Goals; Grant; HIV; HIV-1; HIV-1 Reverse Transcriptase; Highly Active Antiretroviral Therapy; Human; Individual; Institution; Integrase Inhibitors; Latent Virus; Macaca; Macaca mulatta; Measures; Modeling; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Population; Primates; Protease Inhibitor; RNA-Directed DNA Polymerase; Regimen; Research; Research Personnel; Residual state; Resources; Rest; Reverse Transcriptase Polymerase Chain Reaction; SIV; Source; Tissues; United States National Institutes of Health; Viral; Viral load measurement; Viremia; Virus; Virus Replication; antiretroviral therapy; cell type; design; efavirenz; insight; non-nucleoside reverse transcriptase inhibitors; nucleoside analog; pinacolyl methylphosphonic acid; viral DNA; viral RNA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该项目的长期目标是制定和评估从受感染者中根除HIV-1的战略。这些研究将使用动物模型进行，该模型能够全面分析HAART期间的病毒储库和复制动力学。该模型利用被含有HIV-1逆转录酶（RT）代替SIV RT（RT-SHIV）的SIVmac 239嵌合病毒感染的恒河猴。在该模型中，广泛用于人类的三种药物组合[依法韦仑+（-）-FTC + PMPA]在病毒载量（VL）抑制和药物治疗停止后反弹方面模拟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测定法，其检测限为每ml血浆中1-2个病毒RNA（vRNA）拷贝，还开发了灵敏的RT-PCR和PCR测定法来测量组织中的vRNA和病毒DNA（vDNA）。该项目的目标是评估增强的HAART组合，可以更充分地抑制血浆和组织VL的检测水平低于我们的灵敏度PCR检测。由于目前抗逆转录病毒治疗的一个潜在限制是药物进入关键储库组织，我们还将确定靶组织中的药物水平，并利用这些信息优化药物治疗方案。除病毒学终点外，还将在RT-SHIV感染的静息CD 4+淋巴细胞群中评价这些药物组合的影响。重要的是，高度可操作的RT-SHIV/猕猴模型能够通过确定对治疗停止后病毒反弹延迟或减少的影响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）与依法韦仑（NNRTI）或整合酶抑制剂雷特格韦组合的DNA链终止优化; ii）最有效的NRTI与依法韦仑和雷特格韦的组合; iii）与蛋白酶抑制剂或CCR 5拮抗剂的最有效药物组合的增强。该项目的总体假设是，强化的HAART方案有可能从受感染的猕猴中消除RT-SHIV。这些研究将提供关于完全抑制组织和特定细胞类型以及血浆中病毒复制的要求的见解。因此，本项目旨在确定抗病毒药物组合抑制残留病毒血症是否存在局限性，以及根除是否还需要“诱导”策略以重新激活潜伏病毒。