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.

HIV反弹发生在大多数艾滋病毒感染的个体中，在抗逆转录病毒治疗（ART）中断的数周内。 淋巴组织（LT，由淋巴结，扁桃体，腺样体，脾白浆，淋巴骨料组成 外围组织等）是维持和随后的长期HIV的主要部位 水库。虽然我们目前的知识继续进行完善，但受到潜在感染的卵泡助手（TFH）和 LT中的中央记忆（TCM）CD4+ T细胞构成了ART处理的受试者中的大多数储层。 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或其他外围位点。这 血液，周围组织和LT之间淋巴细胞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 淋巴细胞在血液上花费的平均时间仅为60分钟，足够的淋巴细胞进入 来自LT的血液代替了所有血液11倍的人。这种迅速而大规模迁移的影响 淋巴细胞具有HIV免疫致病，根除和治愈的淋巴细胞。我们会在这里 测试（1）淋巴细胞再循环是否允许播种和重新分布感染的CD4+ T细胞 在慢性感染期间或ATI之后，LT的避难所和其他外围储层站点之间，以及（2） 淋巴细胞再循环机制降低了CD8+ T细胞与感染CD4+ T的潜在相互作用 LT内的细胞。我们将抑制ART治疗的SIV感染恒河猕猴（RM）中的淋巴细胞再循环 使用细胞迁移抑制剂fty720 [fingolimod，一种1磷酸受体（S1PR）激动剂]。 FTY720抑制T和B细胞从组织（尤其是LT）中的出口。我们假设FTY720 ATI在SIV感染的RM中的治疗将防止重新激活的HIV感染的CD4+ T细胞离开LT和 保留LT中新激活的SIV特异性CD8+ T细胞。通过使用FTY720，我们将能够 在AIM 1中，定义了抑制淋巴细胞再循环对ATI之后病毒动力学的影响 早期和晚期治疗的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，储层变化，重新激活率，储层多样性和同步 在不同的组织之间，在仅无细胞的情况下，在治疗中断后的储层重新播种， 病毒而不是与细胞相关的，而是可以介导这些作用。在AIM 2中，我们将确定CD8+ T是否 细胞可以限制在早期和/或晚期治疗的SIV之后ATI后LT中的病毒重新激活和反弹 感染。 FTY720会导致CD8+ T细胞在ART中断后保留在LT中。因此，我们可以 确定LT中的CD8+ T细胞是否功能地获得了控制或消除已重新激活的感染的能力 治疗后CD4+ T细胞中断。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。