MOLECULAR EPIDEMIOLOGY AND BIOLOGICAL DETERMINANTS OF HTLV-1

HTLV-1 的分子流行病学和生物学决定因素

• 批准号: 3774873
• 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/3774873
• 关键词: Macaca; biochemical evolution; cell transformation; cytokine receptors; human T cell leukemia; human T cell lymphotropic virus type 1; human tissue; interleukin 2; laboratory mouse; laboratory rabbit; laboratory rat; protein sequence; simian immunodeficiency virus; viral vaccines; virus protein

The study of human T-cell leukemia/lymphotropic virus type I (HTLV-I) and simian T cell leukemia virus type I (STLV-I) molecular evolution is near completion. Further analysis of STLV-I from a few Asian monkey species and pygmy chimpanzees (which are closer to humans than Pan Troglodytes) will be performed. Studies of HTLV-I rabbit models have shifted from pathogenesis to vaccine because 1) rats and mice have been determined to be a more economical model for HTLV-I, and 2) partial success of NYVAC/ALVAC vaccine for protection against human immunodeficiency virus type 2 challenge (see Z01CP05688-03). Major emphasis has been on the functional role of a newly identified protein, p12(I), from the pX region of the HTLV-I genome, which is correlated genetically and functionally to the bovine, papillomavirus 1 (BPV-1) E5 oncoprotein. Further, this small protein, which is located in the golgi complex, binds to a resident protein of the golgi complex, the 16 kilodalton subunit of the proton H+ vacuolar ATPase. Increasing evidence suggests that some viral proteins (E5 of BPV, gp55 of spleen focus forming virus) might function by binding to growth factor receptors and mimic natural ligand function. The possible role of p12(I) in HTLV-l transformation of human T-cells has been investigated by testing its binding to the alpha- and beta-chains of the interleukin 2 (IL-2) receptor. The p12 binds specifically to the IL-2 beta-chain but not to the alpha-chain. We are presently mapping the protein domains involved in these interactions and in parallel trying to develop a transformation assay in hematopoietic cells. The second part of this project involves the development of an HTLV-I vaccine. NYVAC and ALVAC HTLV-I constructs (for background information see Z01CP05688-03) expressing the HTLV-I envelope were used to immunize rabbits. Testing of the immunoresponse against these constructs in the immunized animals with parallel analysis on the natural immunoresponse in humans is ongoing.

人类T细胞白血病/嗜淋巴细胞病毒I型（HTLV-I）和 猿猴 T 细胞白血病病毒 I 型 (STLV-I) 分子进化已接近尾声 完成。对来自几种亚洲猴种的 STLV-I 进行进一步分析 侏儒黑猩猩（比泛穴居人更接近人类） 被执行。 HTLV-I 兔模型的研究已从 疫苗的发病机制是因为 1) 已确定大鼠和小鼠 成为 HTLV-I 的更经济的模型，并且 2) 部分成功 用于预防人类免疫缺陷病毒的 NYVAC/ALVAC 疫苗 2 型挑战（参见 Z01CP05688-03）。 主要重点是 pX 区域新鉴定的蛋白质 p12(I) 的功能作用 HTLV-I 基因组，其在遗传和功能上与 牛乳头瘤病毒 1 (BPV-1) E5 癌蛋白。 此外，这个小 蛋白质位于高尔基复合体中，与居民结合 高尔基复合体的蛋白质，质子 H+ 的 16 千道尔顿亚基 液泡 ATP 酶。 越来越多的证据表明，一些病毒蛋白 （BPV 的 E5、脾病灶形成病毒的 gp55）可能通过结合发挥作用 生长因子受体并模拟天然配体功能。 这 p12(I) 在人类 T 细胞 HTLV-1 转化中的可能作用 通过测试其与α链和β链的结合来研究 白细胞介素 2 (IL-2) 受体。 p12 特异性结合 IL-2 β 链，但不是 α 链。 我们目前正在绘制地图 参与这些相互作用的蛋白质结构域并同时尝试 开发造血细胞转化试验。 该项目的第二部分涉及 HTLV-I 的开发 疫苗。 NYVAC 和 ALVAC HTLV-I 构造（有关背景信息，请参阅 Z01CP05688-03)表达HTLV-I包膜用于免疫 兔子。 测试针对这些构建体的免疫反应 免疫动物的自然免疫反应的平行分析 人类仍在继续。