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Primate Model Towards HIV Eradication Strategies

灵长类动物模型走向艾滋病毒根除策略

基本信息

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
项目类别：
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

项目摘要

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个体中根除HIV-1的战略。这些研究将使用动物模型进行，以便对HAART期间的病毒储存库和复制动力学进行全面分析。该模型利用含有HIV-1逆转录酶（RT）的SIVmac239嵌合病毒感染恒河猴，以取代SIV逆转录酶（RT- shiv）。在这个模型中，广泛用于人类的三种药物组合[efavirenz + (-)- ftc + PMPA]在HIV- 1感染的人类中模拟HAART，在药物治疗停止后抑制病毒载量（VL）和反弹。为了研究RT-SHIV/猕猴模型的根除策略，我们开发了一种灵敏的VL检测方法，其检测限为每ml血浆1-2拷贝病毒RNA (vRNA)，并且还开发了灵敏的RT-PCR和PCR检测方法来测量组织中的vRNA和病毒DNA （vDNA）。该项目的目标是评估HAART联合治疗是否能更充分地将血浆和组织VLs抑制到我们灵敏的PCR检测不到的水平。由于目前抗逆转录病毒疗法的一个潜在限制是药物无法进入关键的储存组织，我们还将确定靶组织中的药物水平，并利用这些信息来优化药物方案。除了病毒学终点外，这些药物组合的影响将在rt - shiv感染的静息CD4+淋巴细胞群体中进行评估。重要的是，高度可操作的RT-SHIV/猕猴模型可以通过确定在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)四种强效核苷类似物（NRTI）与依非韦伦（NNRTI）或整合酶抑制剂雷替格雷韦（raltegravir）联合使用对DNA链终止的优化；ii)最有效的nrti与依非韦伦和雷替重力韦联合使用；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方案有可能消除受感染猕猴体内的RT-SHIV。这些研究将为完全抑制病毒在组织和特定细胞类型以及血浆中的复制提供见解。因此，本项目旨在确定抗病毒药物组合对残留病毒血症的抑制是否存在限制，以及根除是否还需要“诱导”策略来重新激活潜伏病毒。公共卫生相关性：在完全抑制治疗期间，很可能需要完全抑制病毒复制和重新激活潜伏病毒，才能从感染个体中根除HIV-1。该项目的重点是消除细胞和组织中残留的病毒复制。这些结果将为在HAART期间病毒复制和潜伏病毒的其他再激活对残余病毒血症的相对贡献，药物水平与组织和特定细胞类型中病毒抑制的关系，以及强化治疗对静止CD4+ T淋巴细胞潜伏库的影响提供重要信息。这项研究的结果也将有助于未来消除潜伏HIV-1的静息记忆T细胞库的策略研究。这种诱导策略的成功可能取决于完全抑制HAART以防止再激活病毒复制的能力。