Targeting Cytolytic Cells to Lymphoid Sites of HIV Persistence.

将溶细胞细胞靶向 HIV 持续存在的淋巴部位。

基本信息

批准号：
8930055
负责人：
MICHAEL MARCEL LEDERMAN
金额：
$ 26.21万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-19 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8930055
关键词：
Acquired Immunodeficiency Syndrome Address Affect Agonist Anatomy Animals Anti-Retroviral Agents Antiviral Agents Architecture Autopsy B-Lymphocytes Binding Biopsy Blood Blood Circulation Brain CD8B1 gene Caring Cells Chemistry Chronic Clinical Trials Complete Blood Count Complication Control Groups Development Dose Effector Cell Environment Evaluation Exposure to FDA approved Flow Cytometry Goals HIV HIV Infections Health Homeostasis Human Immune Immunohistochemistry Infection Inflammation Inflammatory Intervention Location Lung Lymphocyte Lymphoid Lymphoid Tissue Lymphopenia Lysophospholipids Macaca mulatta Methods Modeling Movement Mucous Membrane Multiple Sclerosis Natural Killer Cells Organ Patients Penetration Pharmaceutical Preparations Phase Phenotype Play Population Primates Regimen Research Research Personnel Residual state Role SIV Safety Serum Site Source Sphingosine-1-Phosphate Receptor Spleen Staining method Stains Study models T-Lymphocyte Testing Therapeutic Time Viral Virus Virus Replication Work animal resource base cytotoxic design dosage experience in vivo indexing longitudinal design lymph nodes nonhuman primate novel novel strategies novel therapeutics receptor rectal replication therapy response safety testing sphingosine 1-phosphate successful intervention

项目摘要

DESCRIPTION: One of the greatest therapeutic challenges in HIV research and care is the goal of viral eradication. Any strategy aimed at HIV eradication in chronic infection will need to address the persistence of virus in secondary lymphoid organs. Eradicating virus from these sites is complicated. Lymph nodes (LN) are rapidly infected in early infection, and maintain residual level of activation/inflammation during ART that may potentiate infection of susceptible cells to sustain the latent reservoir. LN are sites at which penetration of otherwise effective antiretroviral drugs appears limited. A third critical complication is that cytolytic effector T cels are typically excluded from LN by their movement across a concentration gradient of the lysophospholipid sphingosine-1 phosphate (S1P). As a result, lymphoid tissues that constitute critical sites of HIV persistence are relatively protected from HIV-specific cytolytic cells. Based on these findings, we propose a novel approach to retain cytolytic cells in lymphoid tissues by administration of the S1P receptor agonist FTY720. We hypothesize that sustained exposure to cytolytic cells will promote a more inflammatory LN environment, will accelerate the stochastic bursts of SIV replication that play a role in sustaining HIV reservoirs, and will allow cytolytic clls to recognize and destroy virus expressing cells directly in lymphoid tissues. We will test this model in the well-established model of SIV infection of rhesus macaques (RMs) using the S1P receptor agonist FTY720, a molecule approved by the FDA for the treatment of multiple sclerosis that blocks the interaction of S1P with its receptors and results in significant circulatng lymphopenia as a consequence of lymphocyte sequestration in LN. Crucial for this proposal, we developed a fully suppressive ART regimen for SIV-infected RMs, thus validating this model for studies of HIV eradication and cure. In the R21 phase of this proposal, we will assess the safety and activity of two different doses of FTY720 in retaining cytolytic cells in lymphoid tissues in ART-suppressed SIV-infected RMs. If successful, these studies will pave the way for the R33 phase, in which we will determine how FTY720 - at the dose showing the best activity/safety profile in the R21 studies - affects (i) antiviral cytotoxic responses and residual inflammation an (ii) HIV persistence in lymphoid tissues. The longitudinal design will allow analyses of blood, LN and rectal biopsies before and during FTY720 treatment. Elective necropsy after the last dose of FTY720 will give us the unprecedented opportunity to address the effects of FTY720 in many other anatomic locations including spleen, lung and brain.

描述：艾滋病毒研究和护理中最大的治疗挑战之一是病毒辐射的目标。涉及慢性感染中HIV辐射的任何策略都需要解决继发性淋巴器官中病毒的持续性。这些位点的根除病毒很复杂。淋巴结（LN）在早期感染中迅速感染，并在ART期间保持残留的活化/炎症水平，可能会感染易感细胞以维持潜在的储层。 LN是其他有效抗逆转录病毒药物的渗透率似乎有限的部位。第三个临界并发症是细胞溶解效应TCEL通常通过其在溶血磷脂1磷酸盐（S1P）的浓度梯度上运动而排除在LN之外。结果，构成HIV持久性关键部位的淋巴组织相对保护不受HIV特异性细胞溶解细胞的保护。基于在这些发现中，我们提出了一种新的方法，通过给予S1P受体激动剂FTY720保留淋巴组织中的细胞溶细胞。我们假设持续暴露于细胞溶解细胞将促进更具炎性的LN环境，将加速SIV复制的随机爆发，在维持HIV储量中发挥作用，并允许细胞溶性CLL识别和破坏直接在淋巴机组织中表达细胞的病毒。 We will test this model in the well-established model of SIV infection of rhesus macaques (RMs) using the S1P receptor agonist FTY720, a molecule approved by the FDA for the treatment of multiple sclerosis that blocks the interaction of S1P with its receptors and results in significant circulatng lymphopenia as a consequence of lymphocyte session in LN.对于这一建议至关重要的是，我们为感染了SIV感染的RMS开发了一种完全抑制的ART方案，从而验证了该模型的HIV辐射和治疗研究。在该提案的R21阶段，我们将评估两种不同剂量的FTY720在淋巴样组织中的细胞溶解细胞中的安全性和活性。如果成功，这些研究将为R33阶段铺平道路，在该阶段中，我们将确定R21研究中最佳活性/安全性的FTY720如何影响（i）抗病毒细胞毒性反应和残余炎症和（II）HIV的淋巴机组织中的HIV持久性。纵向设计将允许在FTY720治疗之前和期间对血液，LN和直肠活检进行分析。最后一剂FTY720后的选修死刑术将为我们提供前所未有的机会，以解决FTY720在包括脾脏，肺和脑部在内的许多其他解剖区域的影响。