Effects of CSF1R Blockade on Repopulation of SIV Reservoirs from the CNS to the Periphery After Antiretroviral Therapy Interruption

抗逆转录病毒治疗中断后，CSF1R 阻断对中枢神经系统至外周 SIV 储库重新增殖的影响

• 批准号: 10449374
• 负责人: Woong-Ki Kim
• 金额: $ 70.77万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449374
• 关键词: Ablation; Address; Animals; Bone Marrow; Brain; Cells; Cerebrospinal Fluid; Cervical; Color; DNA; Engraftment; FDA approved; HIV; Individual; Infection; Injections; Interruption; Label; Lymph; Lymphatic; Macaca; Macrophage Colony-Stimulating Factor Receptor; Monkeys; Myeloid Cells; Pathway interactions; Patients; Peripheral; Plasma; Population; RNA; Reagent; Residual state; Role; SIV; Source; Spinal Ganglia; Spleen; Testing; Tissues; Viral; Viral reservoir; Viremia; Virus; animal tissue; antiretroviral therapy; deep sequencing; draining lymph node; immunoreactivity; inhibitor; iron oxide nanoparticle; lymphatic drainage; macrophage; migration; prevent; superparamagnetism; trafficking; viral DNA; viral rebound

Abstract Despite effective anti-retroviral therapy (ART) that maintains HIV at non-detectable levels in plasma, HIV is not eradicated. When individuals are off ART, or during viral blips, CNS viral reservoirs can quickly rebound. We and others have found that a population of CNS perivascular macrophages (PVMs) function as a major target for HIV and SIV infection in the CNS, and the viral reservoir that persists with ART. Intracisternal (i.c.) injection of superparamagnetic iron oxide nanoparticles (SPIONs) demonstrate PVMs take up SPIONs within the CNS, accumulate with SIV infection, and traffic out of the CNS where they are found in cervical draining lymph nodes (cLNs), dorsal root ganglia, spleen, and bone marrow. Importantly, SPION-labeled CD163+ macrophages in the cLN can be productively infected with SIV as evidenced by SIV-p27 immunoreactivity. It is our overall hypothesis that an identifiable population of PVMs in the CNS functions as a cellular reservoir of rebound HIV and SIV during ART, and after ART cessation, and these cells can leave the CNS with virus that potentially reseeds the periphery. To test our hypothesis, we propose to use a CNS-penetrant colony-stimulating factor 1 receptor (CSF1R) inhibitor (BLZ945) that ablates these reservoir-reseeding CNS PVM early (3 months after ART initiation) and late (5 months after ART initiation) during ART in virally suppressed macaques, and in animals undergoing ART cessation. We propose to use 2 different fluorescently tagged SPIONs, injected intra-CSF just prior to early and late BLZ945 treatments, in order to define the role of resident and repopulated PVMs to function as a viral reservoir of SIV, and block their ability emigrate with virus. We propose to test our hypothesis with two Specific Aims: Aim 1 will determine the extent to which CSF1R blockade can eradicate SIV in the brain and block lymphatic-dependent reseeding of virus from the CNS to the periphery in the presence of ART; and Aim 2 will determine whether CSF1R blockade can prevent reactivation of SIV reservoirs in the brain and repopulation of viral reservoirs from the CNS to the periphery after ART interruption.

抽象的 尽管有效的抗逆转录病毒疗法 (ART) 可以将血浆中的 HIV 维持在不可检测的水平，但 HIV 并不 根除。当个体停止接受抗逆转录病毒治疗或病毒爆发期间，中枢神经系统病毒库会迅速反弹。我们 等人发现中枢神经系统血管周围巨噬细胞 (PVM) 群体是一个主要目标 针对中枢神经系统中的 HIV 和 SIV 感染，以及 ART 后持续存在的病毒库。脑池内 (i.c.) 注射 超顺磁性氧化铁纳米粒子 (SPION) 证明 PVM 在中枢神经系统内吸收 SPION， SIV 感染时积累，并流出中枢神经系统，在颈部引流淋巴结中发现它们 (cLNs)、背根神经节、脾脏和骨髓。重要的是，SPION 标记的 CD163+ 巨噬细胞 SIV-p27 免疫反应性证明 cLN 可以有效地感染 SIV。这是我们的整体 假设中枢神经系统中可识别的 PVM 群体充当反弹 HIV 的细胞库 ART 期间和 ART 停止后的 SIV，这些细胞可能会带着病毒离开中枢神经系统，这些病毒可能会 重新播种外围。为了检验我们的假设，我们建议使用 CNS 渗透集落刺激因子 1 受体 (CSF1R) 抑制剂 (BLZ945)，可尽早（ART 后 3 个月）消除这些储存库重新播种的 CNS PVM 在病毒抑制的猕猴和动物中，在 ART 期间（ART 开始后 5 个月）和晚期（ART 开始后 5 个月） 正在停止 ART。我们建议使用 2 种不同的荧光标记 SPION，仅注射到脑脊液内 在早期和晚期 BLZ945 治疗之前，为了确定常驻和重新填充的 PVM 发挥功能的作用 作为SIV的病毒储存库，并阻止其随病毒迁移的能力。我们建议用两个方法来检验我们的假设 具体目标：目标 1 将确定 CSF1R 阻断可以在多大程度上根除大脑中的 SIV 并阻断 在存在 ART 的情况下，病毒从中枢神经系统到外周的淋巴依赖性重新播种；目标 2 将 确定 CSF1R 阻断是否可以阻止大脑中 SIV 储库的重新激活和 SIV 的重新增殖 ART 中断后，病毒库从中枢神经系统转移到外周。