Project 2 - Michael Betts

项目 2 - 迈克尔·贝茨

• 批准号: 10224008
• 负责人: Michael R Betts
• 金额: $ 53.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224008
• 关键词: Agonist; B-Lymphocytes; Bar Codes; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Cell physiology; Cells; Data; Disease; Effector Cell; Frequencies; Goals; HIV; Half-Life; Hour; Immune system; Immunologics; Individual; Infection; Interruption; Kinetics; Knowledge; Lymphocyte; Lymphoid; Lymphoid Tissue; Macaca mulatta; Maintenance; Malpighian corpuscles; Mediating; Memory; Movement; Pathogenesis; Peripheral; Plasma; Play; Process; Property; Recrudescences; Role; SIV; Satellite Viruses; Site; Source; Sphingosine-1-Phosphate Receptor; T-Lymphocyte; Testing; Time; Tissues; Tonsil; Viral; Viral reservoir; Viremia; Virus; antiretroviral therapy; base; cell motility; chronic infection; cytotoxic; functional gain; inhibitor/antagonist; insight; lymph nodes; memory CD4 T lymphocyte; migration; peripheral blood; preservation; pressure; prevent; viral rebound

HIV rebound occurs in most HIV infected individuals within weeks of antiretroviral therapy (ART) interruption. Lymphoid tissues (LT, composed of lymph nodes, tonsil, adenoid, splenic white pulp, lymphoid aggregates in peripheral tissues, etc.) are a major site for maintenance and subsequent recrudescence of the long-term HIV reservoir. While our current knowledge continues to be refined, latently infected follicular helper (Tfh) and central memory (Tcm) CD4+ T cells within LT make up the majority of the reservoir in ART treated subjects. Importantly, most T cells are not stationary, and can leave and re-enter LT or other peripheral sites. This process of continual movement of lymphocytes between blood, peripheral tissues, and LT, termed lymphocyte recirculation, is a central process of the immune system. Early studies of lymphocyte recirculation found that the average time a lymphocyte spends in blood is only ~ 60 minutes, and that enough lymphocytes enter the blood from LT to replace all those in blood 11x/day. The impact this rapid and massive migration of lymphocytes has for HIV immunopathogenesis, eradication, and cure remains unstudied. Here we will test whether (1) lymphocyte recirculation allows for the seeding and redistribution of infected CD4+ T cells between sanctuary sites in LT and other peripheral reservoir sites during chronic infection or after ATI, and (2) lymphocyte recirculation mechanisms reduce the potential interaction of CD8+ T cells with infected CD4+ T cells within LT. We will inhibit lymphocyte recirculation in ART-treated SIV-infected rhesus macaques (RM) using the cell migration inhibitor FTY720 [fingolimod, a sphingosine-1 phosphate receptor (S1PR) agonist]. FTY720 inhibits the egress of T and B cells from tissues- especially LT. We hypothesize that FTY720 treatment during ATI in SIV-infected RM will prevent reactivated HIV infected CD4+ T cells from leaving LT and retain newly activated SIV-specific CD8+ T cells in LT. Through the use of FTY720, we will therefore be able to, in Aim 1, define the impact of inhibiting lymphocyte recirculation on viral dynamics following ATI in early and late treated SIV infection. Using barcoded SIVmac239, we will be able to precisely characterize viral rebound kinetics, reservoir changes, reactivation rate, reservoir diversification and synchronization between different tissue, and re-seeding of the reservoir following treatment interruption when only cell-free, rather than cell-associated, virus could mediate these effects. In Aim 2 we will determine whether CD8+ T cells can limit viral reactivation and rebound in LT following ATI in early and/or late treated SIV infection. FTY720 will cause CD8+ T cells to remain in the LT following ART interruption. We can therefore determine whether CD8+ T cells in LT functionally gain the ability to control or eliminate reactivating SIV-infected CD4+ T cells after therapy interruption. Together these studies will provide new insight into the source of viral rebound and potential strategies to control viral rebound.

大多数 HIV 感染者会在抗逆转录病毒治疗 (ART) 中断后几周内出现 HIV 反弹。 淋巴组织（LT，由淋巴结、扁桃体、腺样体、脾白髓、淋巴聚集体组成） 外周组织等）是长期 HIV 维持和随后复发的主要部位 水库。虽然我们目前的知识不断完善，但潜伏感染的卵泡辅助细胞 (Tfh) 和 LT 内的中央记忆 (Tcm) CD4+ T 细胞构成了 ART 治疗受试者的大部分储存库。 重要的是，大多数 T 细胞不是静止的，可以离开并重新进入 LT 或其他外周部位。这 淋巴细胞在血液、外周组织和LT之间持续运动的过程，称为淋巴细胞 再循环，是免疫系统的一个核心过程。淋巴细胞再循环的早期研究发现 淋巴细胞在血液中的平均停留时间仅为约 60 分钟，并且有足够的淋巴细胞进入血液 每天 11 次用 LT 的血液替换血液中的所有血液。这种快速而大规模的迁移所产生的影响 淋巴细胞对于 HIV 免疫发病机制、根除和治愈的作用尚未得到研究。在这里我们将 测试 (1) 淋巴细胞再循环是否允许受感染 CD4+ T 细胞的播种和重新分布 慢性感染期间或 ATI 后 LT 避难所和其他外周储存库位点之间，以及 (2) 淋巴细胞再循环机制减少了 CD8+ T 细胞与感染的 CD4+ T 细胞的潜在相互作用 LT 内的细胞。我们将抑制经 ART 治疗的 SIV 感染恒河猴 (RM) 的淋巴细胞再循环 使用细胞迁移抑制剂 FTY720 [芬戈莫德，一种 1 磷酸鞘氨醇受体 (S1PR) 激动剂]。 FTY720 抑制 T 细胞和 B 细胞从组织（尤其是 LT）中流出。我们假设 FTY720 在 ATI 期间对 SIV 感染的 RM 进行治疗将防止重新激活的 HIV 感染的 CD4+ T 细胞离开 LT 和 在 LT 中保留新激活的 SIV 特异性 CD8+ T 细胞。通过使用 FTY720，我们将能够 在目标 1 中，定义在 ATI 后抑制淋巴细胞再循环对病毒动态的影响 早期和晚期治疗SIV感染。使用条形码 SIVmac239，我们将能够精确表征 病毒反弹动力学、储存库变化、再激活率、储存库多样化和同步化 不同组织之间，以及仅无细胞时治疗中断后重新接种储库， 病毒可以介导这些效应，而不是与细胞相关。在目标 2 中，我们将确定 CD8+ T 是否 在早期和/或晚期治疗的 SIV 中，细胞可以限制 ATI 后的病毒再激活和 LT 反弹 感染。 FTY720 将导致 ART 中断后 CD8+ T 细胞保留在 LT 中。因此我们可以 确定 LT 中的 CD8+ T 细胞是否能够在功能上获得控制或消除重新激活 SIV 感染的能力 治疗中断后 CD4+ T 细胞。这些研究将共同​​提供对来源的新见解 病毒反弹和控制病毒反弹的潜在策略。