ANIMAL MODELS FOR RETROVIRAL PATHOGENESIS, INFECTION AND PREVENTION OF INFECTION

该项目涉及人类和非人类两个主要领域的研究 灵长类逆转录病毒：1)分子遗传学在体内研究中的应用 人类免疫缺陷病毒(HIV)动物模型的致病机制 人T细胞嗜淋巴病毒I型(HTLV-I)及自然感染 被感染的人类。这些研究包括：a)基因操作 HIV-2和猿猴免疫缺陷病毒(SIV)基因组及其序列研究 猪瘟病毒在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)。 在确定病毒滋养能力和传染性方面是必不可少的，以及 SIV包膜中调节细胞杀伤作用的遗传决定因素 SIV的作用；b)一株SIV野外分离株的分子特征 (摘自中国古猿L的Hoesti)及其在恒河猴中的应用； 兔、猴HTLV-I相关动物模型的建立 神经病/热带痉挛截瘫(HAM/TSP)，与脊髓病相关 使用患者的野外病毒分离株而不是 培养适应HTLV-I；和d)病毒表达和分子分析 HAM/TSP和成人T细胞白血病患者的基因漂移2) 开发一种抗艾滋病毒疫苗。其中的向量的选择 表达病毒抗原可能是至关重要的。我们正在寻求几种方法 与包括口服疫苗在内的各种机构合作 (腺病毒疫苗)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媒介株和 首先在猕猴身上测试疗效。 非肠道疫苗：重组禽痘和牛痘病毒。其中一些 媒介也需要在猴子身上单独评估，以研究路线和 运动性感染。各种病毒抗原(纯化的病毒蛋白或 多肽)将单独或与任何 上述载体。

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.