FUNCTIONAL ANALYSIS OF THE HUMAN T-LYMPHOTROPIC VIRUSES

该提案的长期目标是定义HTLV-1的作用， 病毒诱发人类疾病，包括恶性淋巴瘤 和退行性神经系统疾病，并获得转基因小鼠 携带来自这些HTLV样病毒的基因，以描述 发病机理 这项申请由四个具体但相互关联的目标组成： [1]使用转基因小鼠和在单细胞水平上， 原型HTLV-1长末端重复序列（LTR）的组织特异性， 在不存在或存在HTLV-1反式激活剂（tax）的情况下; [2]为了使用转基因小鼠确定HTLV-2和 原型HTLV-1，无论是在LTR的特异性和税收的作用方面 致病基因; [3)为了使用PCR扩增直接从所述细胞克隆HTLV样序列， 涉及热带痉挛性轻瘫（TSP）患者的组织，以及 将其DNA序列与HTLV-1原型进行比较;以及 [4)为了确定使用转基因小鼠的功能意义， 在来自TSP的各种HTLV样序列中检测到的碱基置换 患者，并确定这种替代是否负责 改变疾病表型。

The long term goals of this proposal are to define the role of HTLV-1 like viruses in inducing human disease, including malignant lymphoid neoplasia and degenerative neurological disorders, and to derive transgenic mice carrying genes from these HTLV-like viruses to delineate the mechanisms of disease pathogenesis. This application is composed of four specific but interrelated aims: [1] to define using transgenic mice and at the single cell level the tissue-specificity of the prototype HTLV-1 long terminal repeat (LTR), either in the absence or presence of the HTLV-1 trans-activator (tax); [2] to determine using transgenic mice the differences between HTLV-2 and the prototype HTLV-1, both in terms of LTR specificity and role of the tax gene in inducing pathogenesis; [3) to clone using PCR amplification HTLV-like sequences directly from the involved tissues of patients with Tropical Spastic Paraparesis (TSP), and to compare their DNA sequences with the prototype HTLV-1; and [4) to ascertain using transgenic mice the functional significance of the base substitutions detected among the various HTLV-like sequences from TSP patients, and to determine whether such substitutions are responsible for altering disease phenotypes.