IMMUNE RESPONSE TO HTLV NONSTRUCTURAL PROTEINS

人T细胞白血病病毒L(HTLV-I)是人类T细胞白血病病毒感染的病原体。 成人T细胞白血病与巨细胞病毒L相关性脊髓病/热带痉挛 偏瘫。在感染HTLV-L的人中，只有不到5%的人出现 疾病。其余95%的感染者没有任何症状。 能够传播感染的携带者。对该计划的评估 在动物模型系统中对HTLV-I的免疫反应几乎集中在 独家报道Gag和Env基因产品。然而，对 被感染的人已经表现出显著的，在某些情况下 占主导地位的、体液的和细胞介导的。对病毒的免疫反应 调节蛋白质、税收和税收免疫力与一种 提高了病毒传播的效率。在拟议的研究中，HTLV- 将L感染的兔用于研究Tax基因的表达、免疫 携带者状态下的反应和病毒传播性。我们的假设 是(I)部分HTLV-I感染携带者表达相对较高 税收水平高，病毒传播效率高，并表现出较强的免疫力 对税收的反应；以及(Ii)税收豁免权将减缓或防止 病毒攻击后HTLV-I感染的进展。具体的 该方案的目的是：(1)确定税务基因的动力学 巨噬细胞病毒L感染后的表达。税收基因的表达将通过以下方式衡量 序贯血液和血液中RNA的定量RT-PCR分析 取HTLV-I感染兔的粘膜标本。(2)确定 体液和细胞介导的税收特异性免疫反应的动力学。 从感染HTLV-L的兔身上连续采集血液和粘膜样本将被 用于测量体液和细胞对税收的免疫反应。(3) 确定Tax基因表达、免疫力和 病毒的传播性程度。传染性病毒的存在将 通过与未感染的PBMC共培养来确定，p24水平将 被测量。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 以及对税收的免疫反应。(4)确定之前的免疫接种如何 税收会影响随后的HTLV-I感染。评估一种潜在的HTLV--L 疫苗策略，将对兔子进行税务和肠外免疫 挑战HTLV--L。以下将分析对税收的免疫反应 免疫和挑战。保护将通过共同耕作进行评估 和输血化验。这些研究的结果将提供 有关疫情进展和宿主反应的重要新信息 L在无症状携带者状态下的感染情况。此外，a 将对基于反税收免疫的新疫苗策略进行评估。

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.