CONTROLLING HIV/SIV WITH DRUGS THAT MANIPULATE LYMPHOCYTE TRAFFICKING

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。 基于我们实验室在小鼠/LCMV模型中获得的令人惊讶的结果，该项目旨在测试FTY 720一种阻止淋巴细胞从淋巴结排出的药物，已通过治疗多发性硬化症和预防肾移植排斥反应的II期临床试验增强SIV在慢性感染恒河猴中的免疫控制。 我们发现了一种全新的令人惊讶的免疫疗法，可以完全清除小鼠中的LCMV慢性感染。对于SIV/NHP模式的一年试点项目，我们将重点关注两种治疗模式之一：（1）暴露后立即治疗，或（2）治疗已确定的慢性感染。我们将选择后者，因为（1）它的潜在影响更大（在治疗HIV的背景下），（2）它可能产生更可解释的数据，因为我们将能够确定药物相关的病毒载量变化， 已知的设定点（允许我们使用更少的动物）。 这些实验有三种可能的结果：（1）病毒载量无变化;（2）药物相关的病毒载量增加，可能是由于淋巴结中感染的靶细胞（CD 4+）集中所致;或（3）药物相关的病毒载量降低，如LCMV模型中所示。如果观察到后者，则可能需要进行人体临床试验，这有助于FTY 720在治疗MS和实体器官移植的人体临床试验中进行广泛测试。

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. Building upon surprising results obtained in our laboratory in the mouse/LCMV model, this project is designed to test the ability of FTY720a drug that blocks exit of lymphocytes from lymph nodes and that has been through phase II clinical trials for treating multiple sclerosis and preventing kidney transplant rejectionto enhance the immunological control of SIV in chronically infected rhesus macaques. We had discovered a completely novel and surprising immunotherapy that leads to complete clearance of an otherwise chronic infection of LCMV in the mouse. For a one year pilot project in the SIV/NHP model, we will focus on one of two treatment modes: (1) immediate post-exposure treatment, or (2) treatment of an established of chronic infection. We will choose the latter because of (1) its greater potential impact (in the context of treating HIV), and (2) it is likely to produce data that is more interpretable because we will be able to determine drug-associated changes in viral load relative to known set points (allowing us to use fewer animals). There are three possible results for these experiments: (1) no change in viral load; (2) a drug associated increase in viral load, possibly due to concentrating target cells for infection (CD4+) in lymph nodes; or (3) a drug associated decrease in viral load, as in the LCMV model. If the latter is observed, human clinical trials may be warranted, and it helps that FTY720 has been extensively tested in human clinical trials for treatment of MS and solid organ transplantation.