SIV & HIV 1 RECOMBINANTS SHIVSUBTYPE B ENV

SIV

• 批准号: 6277915
• 负责人: PAUL A LUCIW
• 金额: $ 8.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6277915
• 关键词: AIDS; Mammalia; Primates; immunology; infection; inflammation; lymphatic system; virus

Significance Recombinant SHIVenv clones are a means to analyze the role of HIV-1 env genes in vivo for viral transmission across mucosal membranes and for SAIDS pathogenesis. Additionally, vaccines based on HIV-1 immunogens can be tested for efficacy by challenge with such recombinant viral clones. Objectives An animal model to study both HIV-1 infection and AIDS pathogenesis is not available. To analyze function of specific HIV-1 genes in vivo, SIV/HIV-1 recombinant viruses (designated SHIV) have been constructed by replacing genes in the pathogenic clone SIVmac239 with counterpart HIV-1 genes. We have made SHIV clones containing the envelope (env) gene of various HIV-1 subtype-B isolates, and have analyzed these recombinant viruses in vivo in juvenile and newborn macaques. Results A pathogenic SHIV (designated SHIV-33A), containing the env gene of HIV-1-SF33, was obtained by one passage in a juvenile rhesus macaque. SHIV-33A produced simian AIDS in juvenile macaques when given by either the intravenous or mucosal membrane (oral and vaginal mucosa) routes. In addition, newborn macaques (2 days of age) also developed simian AIDS after intravenous inoculation. Sequence analysis of the env gene of SHIV-33A revealed about 15 amino acid changes, relative to the input SHIV-33 clone. All animals showing immunodeficiency disease also exhibited a rapid and sustained decline in CD4 T-cells in both peripheral blood and lymph nodes. Future Directions Intragenic SHIV-33 recombinants and point mutants, involving the HIV-1SF33 env gene, will be constructed to determine which sequence change(s) accounts for viral adaptation and pathogenesis. Studies will also be performed to determine the mechanism of rapid depletion of CD4 T-cells in the acute stage of infection with the pathogenic SHIV-33A strain; this depletion may be due to either direct cytopathic effects of virus or to indirect mechanisms involving alterations in cytokines in the host. KEYWORDS SHIV, vaccine

意义重组SHIVenv克隆是一种分析 HIV-1 env基因在体内跨粘膜传播中的作用 膜和SAIDS发病机制。 此外，基于 HIV-1免疫原可以通过用这样的抗体进行攻击来测试功效。 重组病毒克隆。 目的建立一种动物模型， HIV-1感染与艾滋病发病机制尚不清楚。 分析 HIV-1特异性基因在体内的功能，SIV/HIV-1重组体 病毒（命名为SHIV）已经通过替换 具有对应HIV-1基因的致病性克隆SIVmac 239。 我们有 制备了含有各种HIV-1包膜基因的SHIV克隆 亚型B分离株，并分析了这些重组病毒， 在幼年和新生猕猴体内。 结果一株致病性SHIV （命名为SHIV-33 A），其含有HIV-1-SF 33的env基因， 通过在幼年恒河猴中一次传代获得。 SIV-33A 在青少年猕猴中产生了猿类艾滋病， 静脉内或粘膜（口腔和阴道粘膜）途径。 在 此外，新生猕猴（2日龄）也出现猴艾滋病 静脉注射后。 猪链球菌env基因的序列分析 SHIV-33 A相对于输入物显示了约15个氨基酸的变化， SHIV-33克隆。 所有显示免疫缺陷疾病的动物也 在两种情况下，CD 4 T细胞均表现出快速和持续的下降， 外周血和淋巴结。 未来方向 SHIV-33重组体和点突变体，涉及HIV-1 SF 33包膜 基因，将被构建以确定哪些序列变化（S） 解释了病毒的适应性和发病机制。 研究还将 以确定CD 4 T细胞快速耗竭的机制 在感染致病性SHIV-33 A株的急性期; 这种消耗可能是由于病毒的直接致细胞病变作用 或间接机制，涉及细胞因子的改变， 主持人 关键词SHIV，疫苗