IMMUNE RESTORATION AND PROTECTION IN SIV-INFECTED LONG TERM NONPROGRESSORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本课题旨在通过对7只感染SIVmac 239的中国恒河猴(CH Rh)的回顾性研究和前瞻性监测，探讨SIVmac感染的中国恒河猴长期无进展(LTNP)的病毒控制和免疫保护机制。我们假设，在同一亚型猕猴中，进展者和LTNP之间的免疫反应的比较将产生信息，这些信息可以直接应用于对抗HIV-1感染的疫苗和治疗策略。我们将测试三个特定目标，1)：比较SIV感染进行期和LTNP CH Rh猕猴黏膜和系统淋巴组织中的功能性病毒特异性和先天免疫反应。对进展者和LTNP的血液、淋巴结和肠道中的病毒特异性T细胞反应和病毒特异性抗体反应进行多色细胞内细胞因子染色。2)：检测和比较SIV感染的进展期猕猴和LTNP CH Rh猕猴黏膜和系统淋巴组织中的基因调控。恒河猴特异的Affymetrix基因阵列芯片将用于检测进展期和LTNP猕猴的粘膜和系统组织。我们假设，特定的基因调控模式将与LTNP相关。3)：检查LTNP和进展者的病毒学因素。可以想象，LTNP可能是“不适合”或突变病毒的出现/优势所致，而不是宿主免疫反应。因此，在病毒血症急性高峰期和病毒抑制的最大时期，将通过细胞培养从LTNP中分离出病毒。我们将在体外比较两个分离株的病毒适合性，我们还将检查病毒序列并分析突变。这将检验一种假设，即宿主特有的免疫机制而不是病毒因素是导致LTNP状态的原因。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this project is to explore the mechanisms of virus control and immune protection in SIVmac-infected long term nonprogressors (LTNP) of Chinese-origin rhesus macaques (Ch Rh) by retrospective study and also prospective monitoring of 7 SIVmac239-infected Ch Rh. We hypothesize that comparison of immune responses between progressors and LTNP within the same subtype of rhesus macaques will yield information, which can be directly applied to vaccine and therapeutic strategies to combat HIV-1 infection. We will test 3 specific aims, 1): To compare functional virus-specific and innate immune responses in both mucosal and systemic lymphoid tissues of SIV-infected progressing, and LTNP Ch Rh macaques. Polychromatic intracellular cytokine staining for virus-specific T cell responses, and virus specific antibody responses will be compared in blood, lymph node, and intestines of progressors and LTNP. 2): To examine and compare gene regulation in mucosal and systemic lymphoid tissues of progressing and LTNP Ch Rh macaques infected with SIV. Rhesus specific Affymetrix gene array chips will be applied to examining mucosal and systemic tissues of progressing and LTNP macaques. We hypothesize that specific patterns of gene regulation will correlate with LTNP. 3): To examine virologic factors in LTNP and progressors. Conceivably, LTNP may result from the emergence/dominance of "unfit" or mutant viruses rather than host immune responses. Thus, viruses will be isolated by cell culture from LTNP at acute peak viremia and during the maximal virus suppression period. We will compare virus fitness of the two isolates in vitro, we will also examine viral sequences and analysis mutations. This will test a hypothesis that host-specific immune mechanisms rather than viral factors are responsible for the LTNP state.