LOSS OF TH1 IMMUNE FUNCTION IN FIV INFECTED CATS

HIV阳性个体被卡氏肺孢子虫和T. 弓形虫是由于T/H1依赖细胞的逐渐侵蚀 介导的免疫系统。大多数研究都集中在侵蚀的 “记忆”免疫反应，这些生物体，但鲜为人知的是， 艾滋病病毒感染时对抗原的初级免疫反应。作为首要 反应在机制上类似于记忆反应，但在 我们预测，对病原体的主要反应是一个更大的 慢病毒诱导的免疫缺陷的灵敏和快速的指标。 对初次免疫应答的研究将提供一种分析 导致HIV相关免疫缺陷的细胞和分子事件 在一个比记忆反应更灵敏更快速的系统中。的关键 这种研究在HIV中是不可行的，是一种动物模型，其中 免疫系统的特定组分可以是表型上的， 在功能上评价了对免疫缺陷诱导的 病毒和继发感染。现有数据表明，FIV 猫的感染提供了这样一个模型。我们有证据表明FIV会导致 猫科动物免疫系统的缺陷会干扰 在受到攻击时， 和T.刚地。我们也有证据表明记忆反应受到损害 FIV感染。我们建议使用FIV-T。弓形虫混合感染模型 研究慢病毒感染中潜在的免疫缺陷 导致初级免疫和记忆免疫的丧失 应答我们将通过研究生殖阶段（血液， 淋巴结，脾）和效应相（肺泡巨噬细胞，肺） 的免疫反应的猫感染FIV，T。，gondii-仅， FIV其次是T. gondii和T.其次是FIV。使用生物测定 对于功能和mRNA的RT-qcPCR，我们将确定细胞因子 这些猫的淋巴和肺组织中的分布。细胞因子反应 将与淋巴细胞的变化和病毒 使用流式细胞仪分析淋巴和肺组织中的表达， 免疫组织化学、原位杂交和病毒感染性 测定。比较这四种基因的表型和功能概况 猫群将有助于确定在T/H1免疫反应中， 发生缺陷（APC功能、克隆缺失、T/H1至T/H2转换）。 它还将决定是否研究的主要免疫反应 可以作为一种敏感、快速的机制来研究HIV诱导的 免疫缺陷。

Infection of HIV+ individuals by organisms such as P. carinii and T. gondii has been attributed to gradual erosion of the T/H1 dependent cell mediated immune system. Most studies have focused on erosion of the "memory" immune response to these organisms, but little is known of the primary immune response to an antigen in HIV infection. As the primary response is mechanistically similar to a memory response, yet greater in magnitude, we predict that the primary response to a pathogen is a more sensitive and rapid indicator of lentivirus-induced immune deficiency. Study of the primary immune response would provide a means to analyze the cellular and molecular events leading to HIV-associated immunodeficiency in a more sensitive and rapid system than a memory response. Critical to such a study, which is not feasible in HIV, is an animal model in which specific components of the immune system can be phenotypically and functionally evaluated in response to both the immunodeficiency-inducing virus and to secondary infections. Existing data indicate that FIV infection of cats provides such a model. We have evidence that FIV causes deficiencies in the feline immune system that interfere with the ability of the cat to mount a protective primary immune response when challenged with T. gondii. We also have evidence that memory response is compromised in FIV infection. We propose to use the FIV-T. gondii co-infection model to examine the underlying immunologic defects in lentivirus infections that lead to the loss of both the primary and the memory immune responses. We will do this by studying both the generation phase (blood, lymph nodes, spleen) and the effector phase (alveolar macrophage, lung) of the immune response in cats infected with FIV-only, T. ,gondii-only, FIV followed by T. gondii, and T. gondii followed by FIV. Using bioassays for function and RT-qcPCR for mRNA, we will determine the cytokine profiles in lymphoid and lung tissue from these cats. Cytokine responses will be correlated with lymphocyte changes and alterations in virus expression in lymphoid and lung tissue using FACS analysis, immunohistochemistry, in situ hybridization, and virus infectivity assays. Comparison of the phenotype and functional profiles of these four groups of cats will help determine where in the T/H1 immune response the defect(s) occurs (APC function, clonal deletion, T/H1 to T/H2 switch). It will also determine whether the study of the primary immune response can be used as a sensitive, rapid mechanism to study HIV-induced immunodeficiency.