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.

摘要 尽管有效的抗逆转录病毒疗法(ART)使艾滋病毒在血浆中保持在无法检测的水平，但艾滋病毒并不是 被根除了。当个人不再接受抗逆转录病毒治疗时，或在病毒发作期间，中枢神经系统病毒库可能会迅速反弹。我们 另一些人发现，一群中枢神经系统血管周围巨噬细胞(PVM)是主要的靶标 针对中枢神经系统中的艾滋病毒和SIV感染，以及持续存在于抗逆转录病毒治疗的病毒库。内侧(I.C.)注射法 超顺磁性氧化铁纳米颗粒(SPION)的研究表明，PVM在中枢神经系统内占据SPION， 随着SIV感染而积聚，并流出中枢神经系统，在颈部引流淋巴结处发现 背根神经节、脾和骨髓。重要的是，Spion标记的CD163+巨噬细胞在 SIV-p27免疫反应性表明，SIV可有效感染CLN。这是我们的整体 中枢神经系统中可识别的PVM群体作为反弹HIV的细胞储存库的假设 和SIV，在ART期间和ART停止后，这些细胞可以离开中枢神经系统，携带有潜在的 重新播种外围设备。为了验证我们的假设，我们建议使用一种中枢神经系统穿透性克隆刺激因子1 受体(CSF1R)抑制剂(BLZ945)早期(ART后3个月)消融这些重新种植的中枢神经PVM 在病毒抑制的猕猴和动物的ART期间(ART开始后5个月)和后期(ART开始后) 正在经历艺术停顿。我们建议使用两种不同的荧光标记SPION，仅在脑脊液中注射 在早期和晚期BLZ945治疗之前，为了确定驻留和重新填充的PVM发挥作用的作用 作为SIV的病毒库，并阻断其携带病毒移民的能力。我们建议用两个例子来检验我们的假设 具体目标：目标1将确定CSF1R阻断在多大程度上可以根除大脑中的SIV并阻断 在ART存在的情况下，淋巴依赖的病毒从中枢神经系统重新接种到外周；AIM 2将 确定CSF1R阻断是否可以防止脑内SIV储存库的重新激活和脑内SIV储存库的重新聚集 ART中断后从中枢神经系统到外围的病毒库。