ANIMAL MODELS FOR RETROVIRAL PATHOGENESIS, INFECTION AND PREVENTION OF INFECTION

逆转录病毒发病、感染和感染预防的动物模型

• 批准号: 3874787
• 负责人: G FRANCHINI
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3874787
• 关键词: AIDS; AIDS vaccines; Bacillus Calmette Guerin vaccine; HIV infections; Macaca; Macaca mulatta; Salmonella typhi; acquired immunodeficiency; disease /disorder model; drug administration routes; genetic manipulation; genetic strain; human T cell leukemia; human T cell lymphotropic virus type 1; human immunodeficiency virus 1; human immunodeficiency virus 2; human tissue; immunological substance; laboratory rabbit; model design /development; neurotropic virus; simian immunodeficiency virus; spastic paralysis; transposon /insertion element; vaccinia virus; virus antigen; virus cytopathogenic effect; virus genetics; virus infection mechanism; virus protein

This project involves two major areas of research on human and non-human primate retroviruses: 1) molecular genetics applied to the study of in vivo pathogenesis in animal models for human immunodeficiency virus (HIV) and human T cell lymphotropic virus type-I (HTLV-I), as well as in naturally infected humans. These studies include: a) genetic manipulations of the HIV-2 and simian immunodeficiency virus (SIV) genome and study of their effect on viral infectivity and pathogenicity in vitro and in vivo in rhesus macaques. For example, we identified accessory genes (vpr, vif) which are essential in determining viral trophism and infectivity, and genetic determinants in the SIV envelope which regulate the cytocidal effect of SIV; b) molecular characterization of a field isolate of SIV (from Cercopithecus L'hoesti) and its use in rhesus macaques; c) development of an animal model rabbit and monkeys) for HTLV-I-associated neuropathy/tropic spastic paraparesis (HAM/TSP), the myelopathy associated to HTLV-I infection using field viral isolates from patients rather than culture adapted HTLV-I; and d) molecular analysis of viral expression and genetic drift in patients with HAM/TSP and adult T cell leukemia. 2) Development of a vaccine against HIV. The choice of the vector in which to express viral antigens might be crucial. We are pursuing several approaches in collaboration with various institutions which include oral vaccines (adenovirus based vaccine) attenuated salmonella typhi and BCG. These vaccines will be prepared with vector strains infectious for macaques and tested for efficacy in macaques first. Parenteral vaccines: Recombinant avipox and vaccinia viruses. Some of these vectors also need to be evaluated alone in monkeys to study the route and the kinetic infection. Various viral antigens (purified viral proteins or peptides) will be evaluated either alone or in conjunction with any of the above mentioned vectors.

该项目涉及人类和非人类两大研究领域 灵长类逆转录病毒：1）分子遗传学应用于体内研究 人类免疫缺陷病毒（HIV）动物模型的发病机制和 人类 T 细胞嗜淋巴细胞病毒 I 型 (HTLV-I)，以及天然存在的病毒 感染人类。这些研究包括：a) HIV-2和猿猴免疫缺陷病毒（SIV）基因组及其研究 体内外对病毒感染性和致病性的影响 恒河猴。例如，我们鉴定了辅助基因（vpr、vif） 这对于确定病毒的营养性和感染性至关重要，并且 SIV 包膜中的遗传决定因素调节细胞杀伤作用 SIV 的影响； b) SIV 现场分离株的分子特征 （来自 Cercopithecus L'hoesti）及其在恒河猴中的应用； c) HTLV-I 相关动物模型兔和猴的开发 神经病/热带性痉挛性截瘫 (HAM/TSP)，与脊髓病相关 使用来自患者的现场病毒分离物来预防 HTLV-I 感染，而不是 培养适应HTLV-I； d) 病毒表达的分子分析和 HAM/TSP 和成人 T 细胞白血病患者的遗传漂变。 2） 开发针对艾滋病毒的疫苗。向量的选择 表达病毒抗原可能至关重要。我们正在寻求几种方法 与包括口服疫苗在内的多个机构合作 （基于腺病毒的疫苗）减毒伤寒沙门氏菌和卡介苗。这些 疫苗将用对猕猴具有传染性的载体菌株制备， 首先在猕猴身上测试了功效。 肠胃外疫苗：重组禽痘病毒和牛痘病毒。其中一些 还需要在猴子中单独评估载体以研究路径和 动力感染。各种病毒抗原（纯化的病毒蛋白或 肽）将单独进行评估或与任何 上述载体。