LONGITUDINAL FOLLOW UP OF SIVMAC PATHOGENESIS IN MACAQUES OF CHINESE ORIGIN

中国猕猴 SIVMAC 发病机制的纵向追踪

• 批准号: 7716197
• 负责人: Binhua Julie Ling
• 金额: $ 6.46万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-21 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716197
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Alleles; Animals; CCR5 gene; CD8B1 gene; Cells; Chinese People; Chronic Phase; Computer Retrieval of Information on Scientific Projects Database; Disease Progression; Flow Cytometry; Funding; Genetic; Grant; Gut associated lymphoid tissue; Haplotypes; Immunogenetics; Infection; Institution; Journals; MHC Class I Genes; Macaca; Macaca mulatta; Measures; Memory; Monkeys; Paper; Pathogenesis; Plasma; Publishing; Recovery; Research; Research Personnel; Resources; SIV; Source; T-Lymphocyte; Testing; United States National Institutes of Health; Universities; Viral; Viral Load result; Wisconsin; day; follow-up; in vivo; restoration; virology

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. We have tested the dynamics of memory CD4+CCR5+ cells (target cells) in GALT in 12 SIV infected Chinese-origin rhesus macaques. Expression of T cell, naive and memory markers were measured by flow cytometry. Eight of 12 monkeys developed AIDS between 6 to 25 months after infection (progressors); 4 were long term nonprogressors (LTNPs) and remained healthy with undetectable plasma viral loads. Memory CD4+ CCR5+ cells were profoundly depleted during acute infection in all 12 monkeys. In progressors, all lacked the ability to maintain restoration of target cells. In the LTNPs, variable memory cell recovery began at day 60 PI and all had restored ¿ 15% of baseline levels by day 180 and maintained this level or increased it. In vivo CD8+ depletion in 2 LNTPs resulted in one to develop AIDS (V542) and the other (AJ07) remains healthy. Our results indicated that profound depletion of target cells in GALT was indistinguishable between progressors and LTNPs in the acute infection. Restoration of target cells during the chronic phase predicted LTNP. Sufficient CD8+ T cells are essential for controlling SIV infection in GALT and required for restoration of target cells. Moreover, host genetic protective factors such as immunogenetics was further studied by analyzing MHC class I alleles, more than 10 new MHC class I locus A and locus B alleles were identified from 9 Chinese-origin rhesus macaques with 48-190 clones per animal. However, when compared progressors with LTNPs, no association of disease progression was found with any particular MHC class I alleles. One recently published paper also indicated that control of simian immunodeficiency virus SIVmac239 is not predicted by inheritance of Mamu-B*17-containing haplotypes by David O'connor's group in the University of Wisconsin (Journal of Virology 2007406-410). Mamu-B*17 was previously recognized as an allele that associated with viral suppression and slow progression.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们检测了12只SIV感染的中国恒河猴GALT中记忆性CD 4 + CCR 5+细胞（靶细胞）的动态。流式细胞术检测T细胞、初始和记忆标志物的表达。12只猴子中有8只在感染后6至25个月之间发展为AIDS（进展者）; 4只为长期非进展者（LTNP），并保持健康，血浆病毒载量检测不到。记忆CD 4 + CCR 5+细胞在所有12只猴的急性感染过程中被严重耗尽。在进展者中，所有人都缺乏维持靶细胞恢复的能力。在LTNP中，可变记忆细胞恢复开始于PI第60天，并且到第180天全部恢复到基线水平的约15%，并且维持该水平或增加该水平。我们的研究结果表明，在急性感染中，GALT中靶细胞的深度耗竭在进展者和LTNP之间是无法区分的。慢性期靶细胞的恢复可预测LTNP。足够的CD 8 + T细胞对于控制GALT中的SIV感染是必不可少的，并且对于靶细胞的恢复是必需的。通过对9只中国恒河猴MHC Ⅰ类基因座的分析，进一步研究了免疫遗传学等宿主遗传保护因素，共鉴定出10余个新的MHC Ⅰ类基因座A和B等位基因，克隆数为48-190个/只。然而，当将进展者与LTNP进行比较时，没有发现疾病进展与任何特定的MHC I类等位基因相关。威斯康星州大学的大卫奥康纳小组最近发表的一篇论文也指出，猴免疫缺陷病毒SIVmac 239的控制不能通过含有Mamu-B*17的单倍型的遗传来预测（病毒学杂志2007 406 -410）。Mamu-B*17以前被认为是与病毒抑制和缓慢进展相关的等位基因。