IMMUNE ACTIVATION IN NEONATAL SIV PATHOGENESIS

最近的数据表明，免疫系统激活在艾滋病毒中起作用 发病机制本提案中至少有两个目标将涉及 这个问题直接在体内模型的艾滋病毒疾病，SIV感染的 恒河猴我们提出两个问题， 活化、凋亡和疾病进展之间的关系：1） 不成熟的免疫系统会支持病毒的复制和发展吗 疾病？也就是说，疾病进展是否需要存在 免疫系统是否能够激活？2）影响是什么 对正在进行的HIV（或SIV）系统添加激活刺激， 感染？在许多体内和体外细胞凋亡的研究中， 艾滋病，细胞活化导致诱导细胞凋亡， 易感细胞群这项工作将继续测试一种机制， 面对细胞凋亡的触发， 激活，并评估粘膜Langerhans细胞在 急性和慢性感染中细胞凋亡诱导。具体目标 是： 1.确定免疫激活对病毒载量和细胞凋亡的影响 在SIV感染的猕猴身上。 2.确定病毒载量、细胞凋亡和疾病进展后， 子宫感染，免疫发展前后 响应能力。 3.测定新生和成年动物的病毒载量和细胞凋亡 经口或静脉感染SIV或SIVdelta 3。 4.比较T细胞系对活化诱导的 用HIV env-阴性构建体感染后的细胞凋亡。 5.确定静息或活化T细胞的感染和凋亡 暴露于急性感染的朗格汉斯细胞;将感染与 nef或vpr缺失的HIV-1或SIVmac 251等基因毒株。 这项拟议中的工作非常重要，因为它将产生新的 胎儿、新生儿和成人慢病毒发病机制的研究进展 感染

Recent data have argued for a role for immune system activation in HIV pathogenesis. At least two of the Aims in this proposal will address this issue directly in an in vivo model of HIV disease, SIV infection of the rhesus macaque. We propose to ask two questions regarding the relationship between activation, apoptosis, and disease progression: 1) Will an immature immune system support viral replication and progression to disease? That is, does disease progression require the presence of an immune system that is capable of activation? and 2) What is the effect of adding an activating stimulus to a system of ongoing HIV (or SIV) infection? In many of the in vivo and in vitro studies of apoptosis in AIDS, cellular activation leads to induction of apoptosis in a susceptible cell population. This work will go on to test a mechanism of viral persistence in the face of triggering of apoptosis by cellular activation, and to assess the role of mucosal Langerhans cells in induction of apoptosis in acute and chronic infection. The Specific Aims are to: 1. Determine the effect of immune activation on viral load and apoptosis in SIV-infected macaques. 2. Determine viral load, apoptosis, and disease progression after in utero infection, before and after the development of immune responsiveness. 3. Determine viral load and apoptosis in neonatal and adult animals infected with SIV or SIVdelta 3 by oral or intravenous infection. 4. Compare susceptibility of T cell lines to activation-induced apoptosis after infection with an HIV env-minus construct. 5. Determine infection and apoptosis of resting or activated T cells exposed to acutely infected Langerhans cells; compare infection with HIV-1 or SIVmac251 with isogenic strains deleted in nef or vpr. The proposed work is highly significant because it will yield new insights into lentiviral pathogenesis in fetal, neonatal, and adult infection.