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Validation of the Rev-dependent vector for targeting SIV macrophage reservoirs

针对 SIV 巨噬细胞储库的 Rev 依赖性载体的验证

基本信息

批准号：
8731441
负责人：
YUNTAO WU
金额：
$ 65.3万
依托单位：
GEORGE MASON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731441
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Anatomy Animal Testing Animals Anti-HIV Agents Behavior Blood Cells Brain Brain Neoplasms Cell Culture Techniques Cells Dendritic Cells Disease Ganciclovir Genetic Recombination Goals Grant HIV HIV Infections HIV Seropositivity HIV tat Protein HIV-1 Herpesviridae Herpesvirus 1 In Vitro Infection Infiltration Injection of therapeutic agent Internal Ribosome Entry Site Knowledge Laboratories LacZ Genes Lead Left Lentivirus Vector Life Life Expectancy Lymphoid Tissue Macaca Macaca mulatta Mediating Modeling Monitor National Institute of Mental Health Neurocognitive Neuronal Injury Neurosurgeon Plasma Prevalence Prevention Primates Prodrugs Production Reporter Research SIV SIV encephalitis Safety Scientist Site Solutions Source Specificity Study Section System T-Lymphocyte TK Gene Testing Thymidine Kinase Tissues Treatment Efficacy Validation Viral Viral Vector Virus antiretroviral therapy base brain cell cell killing experience improved in vivo interest killings macrophage monocyte mouse model nervous system disorder new technology novel novel therapeutics pandemic disease particle prevent public health relevance rev Protein selective expression therapeutic gene vector

项目摘要

DESCRIPTION (provided by applicant): The HIV/AIDS pandemic inflicts approximately 40 million people worldwide. The persistence of HIV in anatomic sanctuary sites such as the brain prevents viral eradication. One of the major natural reservoirs of HIV is macrophages, in particular infected-macrophages infiltrated into the brain also cause neuronal injury. Although the antiretroviral therapy (ART) inhibits viral replication, it does not selectively eliminate vira reservoirs. As such, with the greater life expectancy of infected people, the prevalence of HIV-associated neurological disorder has become a prominent problem. In this proposal, we plan to test a new therapeutic strategy to selectively target viral production and reactivation in the brai in SIV/rhesus macaque model. We have developed a novel HIV/SIV Rev-dependent lentiviral vector carrying therapeutic genes to target HIV/SIV infection. Using this system, we have demonstrated selective killing of HIV-positive cells in cell culture conditions. The proposed research is the first attempt to apply this novel technology to reduce viral persistence in the brain of SIV-infected animals. We plan to test a therapeutic gene, the herpes virus thymidine kinase (HSV1- tk), in rhesus macaques. The Rev-mediated expression of HSV1-tk has the potential to be practically used for the treatment of HIV infection, and may eventually lead to a solution to the disease.

描述（由申请人提供）：艾滋病毒/艾滋病流行病在全世界造成约4000万人的痛苦。艾滋病毒在解剖学上的庇护所（如大脑）中的持续存在阻碍了病毒的根除。HIV的主要天然储存库之一是巨噬细胞，特别是感染的巨噬细胞浸润到大脑中也会导致神经元损伤。虽然抗逆转录病毒疗法（ART）抑制病毒复制，但它不能选择性地消除病毒库。因此，随着感染者预期寿命的延长，与艾滋病毒相关的神经系统疾病的流行已成为一个突出问题。在这项提议中，我们计划测试一种新的治疗策略，以选择性地靶向SIV/恒河猴模型中脑中的病毒产生和再活化。我们已经开发了一种新的HIV/SIV Rev依赖性慢病毒载体，其携带靶向HIV/SIV感染的治疗基因。使用该系统，我们已经证明了在细胞培养条件下选择性杀死HIV阳性细胞。这项研究是首次尝试应用这种新技术来减少SIV感染动物大脑中的病毒持久性。我们计划在恒河猴中测试一种治疗基因，疱疹病毒胸苷激酶（HSV 1- tk）。Rev介导的HSV 1-tk表达具有实际用于治疗HIV感染的潜力，并可能最终导致疾病的解决方案。