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根除病毒的目标。任何旨在根除慢性感染中艾滋病毒的策略都需要解决病毒在次级淋巴器官中的持续存在问题，从这些部位根除病毒是很复杂的。淋巴结 (LN) 在感染早期迅速被感染，并在 ART 期间维持残余的激活/炎症水平，这可能会增强易感细胞的感染，以维持潜伏的淋巴结，这是其他有效细胞渗透的部位。第三个关键并发症是，溶细胞效应 T 细胞通常会通过溶血磷脂鞘氨醇 1 磷酸 (S1P) 的浓度梯度而被排除在淋巴组织之外，从而导致构成 HIV 持续存在的关键位点的淋巴组织。相对免受 HIV 特异性溶细胞细胞的侵害。基于这些发现，我们提出了一种通过施用 S1P 受体激动剂 FTY720 将溶细胞细胞保留在淋巴组织中的新方法，我们发现持续暴露于溶细胞细胞将促进更具炎症性的 LN 环境，将加速 SIV 复制的随机爆发。在维持 HIV 储存库中发挥作用，并使溶细胞细胞能够直接识别和破坏淋巴组织中的病毒表达细胞。我们将在完善的 SIV 感染模型中测试该模型。使用 S1P 受体激动剂 FTY720 治疗恒河猴 (RM)，FTY720 是 FDA 批准用于治疗多发性硬化症的分子，可阻断 S1P 与其受体的相互作用，并因 LN 中淋巴细胞隔离而导致显着的循环淋巴细胞减少。对于这项提案，我们为感染 SIV 的 RM 开发了一种完全抑制性 ART 方案，从而验证了该模型用于 HIV 根除和在该提案的 R21 阶段，我们将评估两种不同剂量的 FTY720 在 ART 抑制的 SIV 感染 RM 中保留淋巴组织中的细胞溶解细胞的安全性和活性。 R33 阶段，我们将确定 FTY720（在 R21 研究中显示出最佳活性/安全性的剂量）如何影响 (i) 抗病毒细胞毒性反应和残留炎症和(ii) 淋巴组织中的 HIV 持续性。纵向设计将允许在 FTY720 治疗前和治疗期间对血液、淋巴结和直肠活检进行分析，这将为我们提供前所未有的机会来解决 FTY720 对许多人的影响。其他解剖位置包括脾、肺和脑。