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

基本信息

批准号：
10643982
负责人：
Woong-Ki Kim
金额：
$ 70.4万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
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

项目摘要

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）使HIV保持在血浆中不可检测的水平，但HIV不是根除。当个人脱离艺术品或在病毒叶片期间，中枢神经系统病毒储层可以迅速反弹。我们其他人发现，CNS周围巨噬细胞（PVM）的主要目标是主要目标对于中枢神经系统中的艾滋病毒和SIV感染，以及与艺术有关的病毒储层。肠内（I.C.）注射超顺磁铁氧化铁纳米颗粒（SPION）表明PVM在中枢神经系统内占用SPION 在SIV感染中积聚，并在CNS中流量出现在宫颈排水淋巴结中（CLN），背根神经节，脾和骨髓。重要的是，Spion标记的CD163+巨噬细胞 SIV-P27免疫反应性证明了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群体充当弹性HIV的细胞库在艺术期间和Art停止之后恢复外围。为了检验我们的假设，我们建议使用CNS-PENETRANT菌落刺激因子1 受体（CSF1R）抑制剂（BLZ945），将这些储层固定的CNS PVM早期（ART后3个月）烧料启动）和在病毒抑制猕猴的艺术期间和动物中的艺术期间（第5个月开始）进行艺术戒烟。我们建议使用2种不同的荧光标记的SPION，仅注入COSF Intra Intra Intra 在BLZ945治疗之前和晚期之前，为了定义居民和重新填充的PVM的作用作为SIV的病毒储存库，并阻止了他们因病毒移民的能力。我们建议用两个具体目的：AIM 1将确定CSF1R封锁可以在大脑中消除SIV的程度在存在艺术的情况下，病毒从中枢神经系统恢复到周围的淋巴依赖性依赖性；和目标2将确定CSF1R封锁是否可以防止大脑中的SIV储层重新激活艺术中断后，病毒储层从中枢神经系统到周围。