Targeting Cytolytic Cells to Lymphoid Sites of HIV Persistence.

 HIV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战略都需要解决次级淋巴器官中病毒的持续存在问题。从这些网站上清除病毒是复杂的。淋巴结（LN）在早期感染中被快速感染，并且在ART期间维持活化/炎症的残余水平，这可能增强易感细胞的感染以维持潜在的储库。LN是其他有效的抗逆转录病毒药物渗透有限的部位。第三个关键的并发症是，溶细胞效应T细胞通常被排除在LN通过它们的运动跨越浓度梯度的溶血磷脂鞘氨醇-1磷酸（S1 P）。因此，构成HIV持续存在的关键部位的淋巴组织相对受到HIV特异性溶细胞细胞的保护。基于 基于这些发现，我们提出了一种新的方法，通过给予S1 P受体激动剂FTY 720来保留淋巴组织中的溶细胞细胞。我们假设持续暴露于溶细胞细胞将促进更多的炎症LN环境，将加速SIV复制的随机爆发，这在维持HIV储库中发挥作用，并将允许溶细胞细胞直接识别和破坏淋巴组织中的病毒表达细胞。我们将使用S1 P受体激动剂FTY 720在恒河猴（RM）的SIV感染的成熟模型中测试该模型，FTY 720是FDA批准用于治疗多发性硬化症的分子，其阻断S1 P与其受体的相互作用，并导致LN中淋巴细胞隔离导致的显著循环淋巴细胞减少。对于这一提议至关重要的是，我们开发了一种针对SIV感染的RM的完全抑制性ART方案，从而验证了这种用于HIV根除和治愈研究的模型。在本提案的R21阶段，我们将评估两种不同剂量的FTY 720在ART抑制的SIV感染RM中保留淋巴组织中溶细胞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R33阶段，我们将确定FTY 720-在R21研究中显示最佳活性/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持久性。纵向设计将允许在FTY 720治疗之前和期间分析血液、LN和直肠活检。FTY 720末次给药后的选择性尸检将为我们提供前所未有的机会，以解决FTY 720在许多其他解剖部位（包括脾、肺和脑）的影响。

 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.