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TRANSGENIC ANTIVIRALS FOR BOVINE LEUKEMIA VIRUS

针对牛白血病病毒的转基因抗病毒药物

基本信息

批准号：
6910528
负责人：
MICHAEL IMBODEN
金额：
$ 20.7万
依托单位：
IOGENETICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2005-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6910528
关键词：
T lymphocyte bovine leukemia virus cow gene expression gene targeting genetically modified animals human T cell lymphotropic virus type 1 regulatory gene transfection /expression vector virus protein virus replication

项目摘要

DESCRIPTION: (Adapted from the applicant's abstract) This fast track combination Phase I and Phase II application has the overall goal of generating transgenic cattle which express the transgene for a transdominant derivative of a regulatory gene from Bovine Leukemia Virus (BLV). The regulatory gene is from the Rex regulatory region that is required for BLV replication and the generation of new infectious virions. The Rex protein functions to mediate the export and expression of viral RNA's, including singly spliced and doubly spliced RNA's that encode the gag, pol, and env proteins. The use of a transdominant derivative of Rex should function to block the function of the mature, native Rex, and thereby inhibit BLV replication. The basis for this relates to studies with the closely related oncovirus, HTLV-1, and studies with its homologous regulatory Rex gene. Transdominant Rex gene expression in HTLV-1 inhibited HTLV-1 replication in vitro. The goals of the phase I application are to generate high titer, replication incompetent vectors that can deliver the engineered BLV Rex and HTLV-1 Rex to cells, and thereby block replication in vitro. The investigators also propose to engineer into the vectors murine MHC class I molecules that will represent a secondary cell surface antigen with the potential of also generating an immune response in vivo. The justification for this is the transdominant delivered Rex will only inhibit active replication, however, latent provirus will not be affected. The expression of the murine MHC molecules will invoke an immune response in cattle and destroy the latently infected cells. In phase II, the applicants propose to produce transgenic cattle expressing TD Rex and evaluate their ability to prevent progressive infection. Since gestation in cattle is 9 months, the applicants also propose to evaluate whether lymphocytes from transgenic cattle can inhibit BLV infection in vitro. Additional, lymphocytes from naturally infected cattle will also be evaluated to determine if the TD Rex vectors can suppress viral replication in vitro. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述：（改编自申请人的摘要）此快速通道结合第一阶段和第二阶段的应用程序的总体目标是产生转基因牛，所述转基因牛表达转基因牛的反式显性衍生物，牛白血病病毒（BLV）的调节基因。调控基因来自 BLV复制所需的雷克斯调控区和产生新的感染性病毒体。雷克斯蛋白的功能是介导病毒RNA的输出和表达，包括单剪接和双剪接编码gag、pol和env蛋白的剪接RNA。的使用雷克斯的转显性导数应该起作用来阻止成熟的天然雷克斯，从而抑制BLV复制。其基础与密切相关的肿瘤病毒HTLV-1的研究以及其同源调控雷克斯基因。HTLV-1中反式显性雷克斯基因的表达抑制HTLV-1的体外复制。第一阶段应用的目标是以产生高滴度、无复制能力的载体，将工程化的BLV雷克斯和HTLV-1雷克斯导入细胞，从而阻断细胞内的复制。体外研究人员还建议将鼠MHC基因工程化到载体中 I类分子，其将代表第二细胞表面抗原，也可能在体内产生免疫应答。的理由这是反式显性传递的雷克斯只会抑制主动复制，然而，潜伏前病毒不会受到影响。小鼠MHC的表达分子将引起牛的免疫反应，并破坏潜在的被感染的细胞在第二阶段，申请人提出生产转基因的表达TD雷克斯的牛，并评估其预防进行性感染由于牛的妊娠期为9个月，申请人还提出评价转基因牛的淋巴细胞是否能抑制BLV 体外感染。此外，来自自然感染牛的淋巴细胞将还可以评估以确定TD雷克斯载体是否可以抑制病毒体外复制。拟议商业应用：不可用