LONGITUDINAL FOLLOW UP OF SIVMAC PATHOGENESIS IN MACAQUES OF CHINESE ORIGIN

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。 我们检测了12只感染SIV的中国恒河猴GALT中记忆的CD4+CCR5+细胞(靶细胞)的动态变化。用流式细胞仪检测T细胞、幼稚细胞和记忆标志物的表达。12只猴子中有8只在感染后6至25个月内出现艾滋病(进展者)；4只长期无进展者(LTNPs)，在无法检测到血浆病毒载量的情况下保持健康。在急性感染期间，所有12只猴子的记忆中的CD4+CCR5+细胞都严重耗尽。在进展者中，所有人都缺乏维持靶细胞恢复的能力。在LTNPs中，可变记忆细胞恢复开始于第60天，到第180天，所有人都恢复了基线水平的15%，并维持或增加了这一水平。在体内，2个LNTP中的CD8+耗尽导致1个患艾滋病(V542)，另一个(AJ07)健康。我们的结果表明，在急性感染中，进展型和LTNPs之间无法区分GALT靶细胞的深度耗竭。慢性期靶细胞的恢复可预测LTNP。足够的CD8+T细胞是控制SIV感染所必需的，也是恢复靶细胞所必需的。此外，通过对MHC I类等位基因的分析，进一步研究了免疫遗传学等宿主遗传保护因素，从9只中国恒河猴48-190个克隆中鉴定出10多个新的MHC I类A、B等位基因。然而，当将进展者与LTNPs进行比较时，没有发现疾病进展与任何特定的MHC I类等位基因有关。最近发表的一篇论文也指出，威斯康星大学的大卫·奥康纳研究小组(《病毒学杂志》2007406-410)不能通过遗传含有Mamu-B*17的单倍型来预测SIVmac239病毒的控制。此前，Mamu-B*17被认为是与病毒抑制和缓慢进展相关的等位基因。

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. 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.