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感染者在抗逆转录病毒治疗（ART）中断的几周内发生HIV反弹。 类淋巴组织（LT，由淋巴结、扁桃体、腺样体、脾白色髓、淋巴样聚集体组成， 外周组织等）是长期HIV病毒维持和随后复发的主要场所 水库虽然我们目前的知识不断完善，潜伏感染的卵泡辅助细胞（Tfh）和 LT内的中央记忆（Tcm）CD 4 + T细胞构成ART治疗受试者中的大部分储库。 重要的是，大多数T细胞不是静止的，并且可以离开和重新进入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中心过程。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时间只有60分钟，足够的淋巴细胞进入血液， 从LT中抽取血液，以11 x/天替换血液中的所有血液。这种快速而大规模的移民 淋巴细胞对HIV免疫发病机制、根除和治愈的作用尚未研究。这里我们将 测试（1）淋巴细胞再循环是否允许受感染的CD 4 + T细胞的接种和再分布 在慢性感染期间或ATI后，LT中的庇护部位与其他外周储库部位之间的差异，以及（2） 淋巴细胞再循环机制降低了CD 8 + T细胞与受感染的CD 4 + T细胞的潜在相互作用 我们将抑制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FTY 720 [芬戈莫德，鞘氨醇-1磷酸受体（S1 PR）激动剂]。 FTY 720抑制T细胞和B细胞从组织中流出，尤其是LT。 在ATI期间对SIV感染的RM的治疗将阻止再活化的HIV感染的CD 4 + T细胞离开LT， 保留LT中新激活的SIV特异性CD 8 + T细胞。通过使用FTY 720，我们因此能够 在目的1中，定义ATI后抑制淋巴细胞再循环对病毒动力学的影响， 早期和晚期治疗SIV感染。使用条形码SIVmac 239，我们将能够精确地表征 病毒反弹动力学、库变化、再激活率、库多样化和同步化 在不同组织之间，以及当仅无细胞时在治疗中断后重新接种储库， 而不是细胞相关的，病毒可以介导这些作用。在目标2中，我们将确定CD 8 + T细胞是否 细胞可以限制早期和/或晚期治疗的SIV中ATI后LT中的病毒再活化和反弹 感染FTY 720将在ART中断后导致CD 8 + T细胞保留在LT中。因此我们可以 确定LT中的CD 8 + T细胞是否在功能上获得控制或消除再活化SIV感染的能力， 治疗中断后的CD 4 + T细胞。这些研究将为我们提供新的视角， 以及控制病毒反弹的潜在策略。