Macrophage-mediated delivery of HIV-1 Vaccine

巨噬细胞介导的 HIV-1 疫苗递送

• 批准号: 6906486
• 负责人: Malgorzata Simm
• 金额: $ 20.18万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906486
• 关键词: AIDS therapy; AIDS vaccines; HIV infections; R factors; SDS polyacrylamide gel electrophoresis; affinity chromatography; drug vehicle; human tissue; immunoprecipitation; macrophage; mass spectrometry; molecular cloning; nuclear factor kappa beta; polymerase chain reaction; recombinant proteins; tumor necrosis factor alpha; virus replication

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HA ART) has been effective in decreasing the incidence of Central Nervous System (CNS) complications due to HIV-1 infection. However, a significant proportion of patients on HAART still progress to HIV-associated dementia (HAD), indicating the need for more effective treatment of HIV-1 infection in the CNS. We have induced the synthesis of an endogenous cellular inhibitor of HIV- 1 replication in immortalized CD4vT lymphocytes by co-cultivation with peripheral blood lymphocytes (PBL) chronically infected with an attenuated HIV-1. Resistant cells secrete constitutively a soluble antiviral factor named HRF (HIV-1 Resistance Factor) that inhibits the replication of X4 and R5 laboratory strains of HIV-1 and patient isolates in vitro. After first review of this application, we identified hrf as a human homologue of arabidopsis thaliana glp-like binding protein. Our studies indicate that HRF interferes with NFkappaB transactivation of transcription of cellular genes and stops the LTR driven transcription of HIV-1 genes, The antiviral effect of HRF has been observed in vitro in several types of T cells by inhibition of HIV-1 LTR promoted expression of reporter genes and by inhibition of 4alpha-phorbol 12-myristate 13- acetate (PMA) induced expression of the latent HIV-1 in ACH-2 cells. Our recent preliminary data indicate that HRF also acts as an effective inhibitor of HIV-1 infection in primary human macrophages and fetal astrocytes. These observations suggest that HRF is a promising candidate for a new drug targeting both HIV-1 and NFKappaB-mediated induction of neuroinflammatory molecules such as TNF-alpha in the CNS. This exploratory project proposes: (1) to clone and express recombinant hrf; (2) To study the mechanism of HRF mediated inhibition of HIV-1 and TNF-alpha in vitro in macrophages;. The long-term goal of this project is to employ HRF as a novel inhibitor of both HIV replication and inflammation in the brain.

描述（由申请人提供）：高度活跃的抗逆转录病毒疗法（HA ART）已有效降低因HIV-1感染引起的中枢神经系统（CNS）并发症的发生率。但是，HAART的大部分患者仍然发展为与HIV相关的痴呆（HAT），表明需要更有效地治疗CNS中的HIV-1感染。我们通过与外周血血液淋巴细胞（PBL）共培养，诱导了永生化的CD4VT淋巴细胞中HIV-1复制的内源性细胞抑制剂的合成。抗性细胞分泌组成型的一种可溶性抗病毒因子，称为HRF（HIV-1抗性因子），该因子抑制了HIV-1的X4和R5实验室菌株的复制，并在体外抑制了HIV-1和患者分离株的复制。在首次审查了该应用后，我们将HRF确定为拟南芥GLP样结合蛋白的人类同源物。我们的研究表明，HRF干扰了细胞基因转录的NFKappab并停止HIV-1基因的LTR驱动的转录，HRF的抗病毒效应已通过抑制HIV-1 LTR的抑制作用和抑制4pha-pha-pha的表达，在几种类型的T细胞中观察到了HRF的抗病毒效应。潜在HIV-1在ACH-2细胞中的表达。我们最近的初步数据表明，HRF在原发性巨噬细胞和胎儿星形胶质细胞中也充当了HIV-1感染的有效抑制剂。这些观察结果表明，HRF是针对HIV-1和NFKAPPAB介导的神经炎症分子（例如CNS中TNF-Alpha）的新药的有前途的候选者。该探索性项目提出：（1）克隆并表达重组HRF； （2）研究巨噬细胞中HRF介导的HIV-1和TNF-Alpha的抑制作用；该项目的长期目标是利用HRF作为大脑中HIV复制和炎症的新型抑制剂。