SIV & HIV 1 RECOMBINANTS SHIVSUBTYPE B ENV

SIV

• 批准号: 6116674
• 负责人: PAUL A LUCIW
• 金额: $ 7.98万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116674
• 关键词: AIDS; Mammalia; communicable diseases; immunology; 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. In vitro analysis of SHIV-33A revealed increased cytopathicity and increased replication in tissue culture cells. Future Directions Intragenic SHIV-33 recombinants and point mutants, involving the HIV-1SF33 env gene, are being 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. Functional domains of SHIV-33A will be analyzed by constructing env genes with point and deletion mutations; these mutant viral clones will be examined in tissue culture cells and in rhesus macaques. KEY WORDS HIV-1 genes, AIDS pathogenesis, SHIV clones FUNDING NIH Grant AI41907

意义：重组SHIVenv克隆是一种分析病毒的方法