Targeting Cytolytic Cells to Lymphoid Sites of HIV Persistence.

 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的艾滋病毒的战略都需要解决次级淋巴器官中病毒的持久性问题。从这些地方根除病毒是很复杂的。淋巴结节(LN)在感染早期迅速被感染，并在ART过程中保持残余的激活/炎症水平，这可能会加强对敏感细胞的感染，以维持潜伏的储存库。LN是其他有效的抗逆转录病毒药物渗透似乎有限的部位。第三个关键并发症是细胞溶解效应T细胞通过溶血磷脂鞘氨醇-1磷酸(S1P)的浓度梯度移动而典型地被排除在LN之外。因此，构成艾滋病毒持续存在的关键部位的淋巴组织相对受到艾滋病毒特异性细胞溶解细胞的保护。基座 根据这些发现，我们提出了一种新的方法，通过给予S1P受体激动剂FTY720来保留淋巴组织中的细胞溶解细胞。我们假设，持续暴露于溶细胞性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，从而在维持HIV宿主方面发挥作用，并将允许溶细胞性CLL识别并直接破坏淋巴组织中表达病毒的细胞。我们将使用S1P受体激动剂FTY720在恒河猴SIV感染(RMS)的成熟模型中测试这一模型，FTY720是FDA批准用于治疗多发性硬化症的分子，它阻止S1P与其受体的相互作用，并由于LN中的淋巴细胞隔离而导致显著的循环淋巴细胞减少。对这项建议至关重要的是，我们为SIV感染的RMS开发了一种完全抑制ART方案，从而验证了该模型用于艾滋病毒根除和治愈的研究。在这项建议的R21阶段，我们将评估两种不同剂量的FTY720在ART抑制的SIV感染的RMS中保留淋巴组织中的细胞溶解细胞的安全性和活性。如果成功，这些研究将为R33阶段铺平道路，在这一阶段，我们将确定FTY720-在R21研究中显示最佳活性/安全概况的剂量-如何影响(I)抗病毒细胞毒反应和残余炎症，以及(Ii)淋巴组织中HIV的持久性。纵向设计将允许对FTY720治疗前和治疗期间的血液、LN和直肠活检进行分析。最后一剂FTY720后的选择性尸检将给我们提供前所未有的机会来解决FTY720在许多其他解剖位置的影响，包括脾、肺和脑。

 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.