ANIMAL MODELS FOR RETROVIRAL PATHOGENESIS, INFECTION AND PREVENTION OF INFECTION

这个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， 人T细胞嗜淋巴细胞病毒I型（HTLV-I），以及在天然 被感染的人类这些研究包括：a）基因操作的 HIV-2和猴免疫缺陷病毒（SIV）基因组及其研究进展 在体外和体内对病毒感染性和致病性影响 恒河猴例如，我们鉴定了辅助基因（vpr，vif） 其在确定病毒的营养性和感染性中是必需的， SIV包膜中调节杀细胞因子的遗传决定簇 SIV影响; B）SIV田间分离物的分子表征 (from Cercopithecus L 'hoesti）及其在恒河猴中的用途; c） HTLV-I相关的动物模型（兔和猴）的开发 神经病/热带痉挛性轻瘫（HAM/TSP），脊髓病相关 使用来自患者的田间病毒分离物，而不是 培养适应的HTLV-I;和d）病毒表达的分子分析， HAM/TSP和成人T细胞白血病患者的遗传漂变。（二） 研制艾滋病毒疫苗。选择的载体， 表达病毒抗原可能至关重要。我们正在采取几种方法 与包括口服疫苗在内的各种机构合作 （基于腺病毒的疫苗）减毒伤寒和BCG。这些 疫苗将用对猕猴有感染性的载体菌株制备， 首先在猕猴身上进行了有效性测试 胃肠外疫苗：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，以研究途径， 动力学感染各种病毒抗原（纯化的病毒蛋白或 肽）将单独或与任何 以上提到的载体。

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.