IMMUNE RESPONSE TO HTLV NONSTRUCTURAL PROTEINS

人T细胞白血病病毒I型（HTLV-I）是T细胞白血病的病原体， 成人T细胞白血病和HTLV-1相关的脊髓病/热带痉挛 下肢轻瘫不到5%的HTLV-1感染个体发展为 疾病其余95%感染者无症状 能够传播感染的带菌者。评价 在动物模型系统中对HTLV-I的免疫应答几乎集中在 专门针对Gag和Env基因产物。 然而，研究 受感染的人类表现出显著的，在某些情况下， 主要是体液和细胞介导的。对病毒的免疫反应 调节蛋白，税收，和免疫税收已与一个 提高病毒传播的效率。在拟议的研究中，HTLV- l感染兔将用于研究Tax基因表达、免疫 反应和病毒在载体状态下的传播性。我们的假设 （i）一部分HTLV-I感染的携带者表达相对高的 水平的税收，有效地传播病毒，并显示出很强的免疫力 （二）税收减免将减缓或阻止 病毒攻击后HTLV-I感染的进展。具体 目的：（1）确定Tax基因的动力学 HTLV-1感染后的表达。Tax基因表达将通过以下方法测量： 定量RT-PCR分析从连续的血液中分离的RNA， 从HTLV-1感染的兔获得的粘膜样品。(2)确定 体液和细胞介导的Tax特异性免疫应答的动力学。 将来自HTLV-1感染的兔的连续血液和粘膜样品进行分析。 用于测量对Tax的体液和细胞介导的免疫应答。（三） 确定Tax基因表达、免疫力和肿瘤细胞凋亡之间的关系。 病毒传播的程度。 感染性病毒的存在将 通过与未感染的PBMC共培养来确定，并且p24水平将 被衡量。具体目标1、2和3的结果将与 评估基因表达是否与病毒传播性相关 和对税收的免疫反应 (4)确定先前的免疫接种 税收影响随后的HTLV-I感染。评估一种可能的HTLV-1 疫苗策略，将用Tax对家兔进行胃肠外免疫， 用HTLV-1攻击。对税收的免疫应答将在以下分析 免疫和挑战。保护将通过共培养进行评估 和输血测定。这些研究的结果将提供 关于进展和宿主反应的重要新信息 无症状携带者状态下的HTLV-1感染。另外还有按 将评估基于抗Tax免疫的新型疫苗策略。

Human T cell leukemia virus type l (HTLV-I) is the etiologic agent of adult T cell leukemia, and HTLV-l associated myelopathy/tropical spastic paraparesis. Less than 5% of HTLV-l infected individuals develop either disease. The remaining 95% of infected individuals are asymptomatic carriers who are capable of transmitting infection. Evaluation of the immune response to HTLV-I in animal model systems has focused almost exclusively on the Gag and Env gene products. However, studies of infected humans have demonstrated significant, and in some cases predominant, humoral and cell-mediated. immune responses to the viral regulatory protein, Tax, and immunity to Tax has been associated with an increased efficiency of virus transmission. In the proposed studies, HTLV- l infected rabbits will be used to investigate Tax gene expression, immune responses and virus transmissibility in the carrier state. Our hypotheses are (i) that a portion of HTLV-I infected carriers express relatively high levels of Tax, transmit the virus efficiently, and display a strong immune response to Tax, and (ii) that immunity to Tax will slow or prevent progression of HTLV-I infection following viral challenge. The specific aims of the proposal are to: (1) Determine the kinetics of Tax gene expression after HTLV-l infection. Tax gene expression will be measured by quantitative RT-PCR analysis of RNA isolated from sequential blood and mucosal samples obtained from HTLV-I infected rabbits. (2) Determine the kinetics of humoral and cell mediated Tax-specific immune responses. Sequential blood and mucosal samples from HTLV-l infected rabbits will be used to measure the humoral and cell-mediated immune response to Tax. (3) Determine the relationship between Tax gene expression, immunity, and the degree of virus transmissibility. The presence of infectious virus will be determined by co-cultivation with uninfected PBMC, and p24 levels will be measured. The results of specific aims 1, 2, and 3 will be compared to evaluate whether gene expression correlates with virus transmissibility and immune responses to Tax. (4) Determine how prior immunization with Tax affects a subsequent HTLV-I infection. To evaluate a potential HTLV-l vaccine strategy, rabbits will be parenterally immunized with Tax and challenged with HTLV-l. Immune responses to Tax will be analyzed following immunization and challenge. Protection will be evaluated by co-cultivation and transfusion assays. The results of these studies will provide important new information regarding progression of, and host response to HTLV-l infection during the asymptomatic carrier state. In addition, a novel vaccine strategy based on anti-Tax immunity will be evaluated.